Article

Distinct Roles for Spontaneous and Visual Activity in Remodeling of the Retinogeniculate Synapse

November 2006
Neuron 52(2):281-91

November 2006
52(2):281-91

DOI:10.1016/j.neuron.2006.07.007

Source
PubMed

Authors:

Bryan M Hooks

Howard Hughes Medical Institute

Sensory experience and spontaneous activity play important roles in development of sensory circuits; however, their relative contributions are unclear. Here, we test the role of different forms of activity on remodeling of the mouse retinogeniculate synapse. We found that the bulk of maturation occurs without patterned sensory activity over 4 days spanning eye opening. During this early developmental period, blockade of spontaneous retinal activity by tetrodotoxin, but not visual deprivation, retarded synaptic strengthening and inhibited pruning of excess retinal afferents. Later in development, synaptic remodeling becomes sensitive to changes in visually evoked activity, but only if there has been previous visual experience. Synaptic strengthening and pruning were disrupted by visual deprivation following 1 week of vision, but not by chronic deprivation from birth. Thus, spontaneous activity is necessary to drive the bulk of synaptic refinement around the time of eye opening, while sensory experience is important for the subsequent maintenance of connections.

Activity-induced MeCP2 phosphorylation regulates retinogeniculate synapse refinement

Article

Full-text available

Oct 2023

Mutations in MECP2 give rise to Rett syndrome (RTT), an X-linked neurodevelopmental disorder that results in broad cognitive impairments in females. While the exact etiology of RTT symptoms remains unknown, one possible explanation for its clinical presentation is that loss of MECP2 causes miswiring of neural circuits due to defects in the brain’s capacity to respond to changes in neuronal activity and sensory experience. Here, we show that MeCP2 is phosphorylated at four residues in the mouse brain (S86, S274, T308, and S421) in response to neuronal activity, and we generate a quadruple knock-in (QKI) mouse line in which all four activity-dependent sites are mutated to alanines to prevent phosphorylation. QKI mice do not display overt RTT phenotypes or detectable gene expression changes in two brain regions. However, electrophysiological recordings from the retinogeniculate synapse of QKI mice reveal that while synapse elimination is initially normal at P14, it is significantly compromised at P20. Notably, this phenotype is distinct from the synapse refinement defect previously reported for Mecp2 null mice, where synapses initially refine but then regress after the third postnatal week. We thus propose a model in which activity-induced phosphorylation of MeCP2 is critical for the proper timing of retinogeniculate synapse maturation specifically during the early postnatal period.

Primary Visual Cortex Modules in Mammals

Article

Full-text available

Jul 2023

Natalia Merkulyeva

Activity-Induced MeCP2 Phosphorylation Regulates Retinogeniculate Synapse Refinement

Preprint

Jul 2023

Unlabelled: Mutations in MECP2 give rise to Rett syndrome (RTT), an X-linked neurodevelopmental disorder that results in broad cognitive impairments in females. While the exact etiology of RTT symptoms remains unknown, one possible explanation for its clinical presentation is that loss of MeCP2 causes miswiring of neural circuits due to defects in the brain's capacity to respond to changes in neuronal activity and sensory experience. Here we show that MeCP2 is phosphorylated at four residues in the brain (S86, S274, T308, and S421) in response to neuronal activity, and we generate a quadruple knock-in (QKI) mouse line in which all four activity-dependent sites are mutated to alanines to prevent phosphorylation. QKI mice do not display overt RTT phenotypes or detectable gene expression changes in two brain regions. However, electrophysiological recordings from the retinogeniculate synapse of QKI mice reveal that while synapse elimination is initially normal at P14, it is significantly compromised at P20. Notably, this phenotype is distinct from that previously reported for Mecp2 null mice, where synapses initially refine but then regress after the third postnatal week. We thus propose a model in which activity-induced phosphorylation of MeCP2 is critical for the proper timing of retinogeniculate synapse maturation specifically during the early postnatal period. Significance statement: Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that predominantly affects girls. RTT is caused by loss of function mutations in a single gene MeCP2. Girls with RTT develop normally during their first year of life, but then experience neurological abnormalities including breathing and movement difficulties, loss of speech, and seizures. This study investigates the function of the MeCP2 protein in the brain, and how MeCP2 activity is modulated by sensory experience in early life. Evidence is presented that sensory experience affects MeCP2 function, and that this is required for synaptic pruning in the brain. These findings provide insight into MeCP2 function, and clues as to what goes awry in the brain when the function of MeCP2 is disrupted.

Mechanism of microglia-neuron interaction at the node of Ranvier

Thesis

Full-text available

Jan 2022

Rémi Ronzano

Multiple sclerosis is an inflammatory and neurodegenerative disease of the central nervous system. Although therapies reducing the inflammatory component of the disease are available, it is essential to understand the mechanisms promoting remyelination in order to develop strategies to slow down the progression of the disease. The nodes of Ranvier allow the fast saltatory propagation of action potentials along myelinated fibers. It has been shown that nodes are an early target in demyelination that induces their disruption. Furthermore, it was observed that the reclustering of the nodes is an early event in remyelination suggesting a role in repair. Microglia are the resident immune cells of the central nervous system and are key regulators of remyelination. The interaction of microglial cells with neurons is known to modulate several physiological and pathological mechanisms. Therefore, we hypothesized that microglia may interact with nodes of Ranvier, and that this interaction could regulate microglial physiology and indirectly remyelination. Here, we have identified that microglia interact with nodes throughout the central nervous system and that these contacts are reinforced during remyelination. Furthermore, along myelinated axons, we found that microglia interact preferentially with nodes and that this interaction is modulated by neuronal activity through potassium fluxes. During remyelination, the inhibition of microglia-node interaction correlates with an inhibition of the microglial switch and of remyelination efficiency suggesting a potential role of microglia-node interaction in repair.

Neurotransmitter regulation rather than cell‐intrinsic properties shapes the high‐pass filtering properties of olfactory bulb glomeruli

Article

Full-text available

Dec 2021
J PHYSIOL-LONDON

GABAergic periglomerular (PG) cells in the olfactory bulb are proposed to mediate an intraglomerular ‘high‐pass’ filter through inhibition targeted onto a glomerulus. With this mechanism, weak stimuli (e.g. an odour with a low affinity for an odourant receptor) mainly produce PG cell‐driven inhibition but strong stimuli generate enough excitation to overcome inhibition. PG cells may be particularly susceptible to being activated by weak stimuli due to their intrinsically small size and high input resistance. Here, we used dual‐cell patch‐clamp recordings and imaging methods in bulb slices obtained from wild‐type and transgenic rats with labelled GABAergic cells to test a number of predictions of the high‐pass filtering model. We first directly compared the responsiveness of PG cells with that of external tufted cells (eTCs), which are a class of excitatory cells that reside in a parallel but opposing position in the glomerular circuitry. PG cells were in fact found to be no more responsive than eTCs at low levels of sensory neuron activity. While PG cells required smaller currents to be excited, this advantage was offset by the fact that a given level of sensory neuron activity produced much smaller synaptic currents. We did, however, identify other factors that shaped the excitation/inhibition balance in a manner that would support a high‐pass filter, including glial glutamate transporters and presynaptic metabotropic glutamate receptors. We conclude that a single glomerulus may act as a high‐pass filter to enhance the contrast between different olfactory stimuli through mechanisms that are largely independent cell‐intrinsic properties. Key points GABAergic periglomerular (PG) cells in the olfactory bulb are proposed to mediate a ‘high‐pass’ filter at a single glomerulus that selectively blocks weak stimulus signals. Their efficacy may reflect their intrinsically small size and high input resistance, which allows them to be easily excited. It was found that PG cells were in fact no more likely to be activated by weak stimuli than excitatory neurons. PG cells fired action potentials more readily in response to a fixed current input, but this advantage for excitability was offset by small synaptic currents. Glomeruli nevertheless display an excitation/inhibition balance that can support a high‐pass filter, shifting from unfavourable to favourable with increasing stimulus strength. Factors shaping the filter include glial glutamate transporters and presynaptic metabotropic glutamate receptors. It is concluded that a single glomerulus may act as a high‐pass filter to enhance stimulus contrast through mechanisms that are largely independent of cell‐intrinsic properties.

Phospholipid‐flippase chaperone CDC50A is required for synapse maintenance by regulating phosphatidylserine exposure

Article

Sep 2021

Synaptic refinement is a critical physiological process that removes excess synapses to establish and maintain functional neuronal circuits. Recent studies have shown that focal exposure of phosphatidylserine (PS) on synapses acts as an "eat me" signal to mediate synaptic pruning. However, the molecular mechanism underlying PS externalization at synapses remains elusive. Here, we find that murine CDC50A, a chaperone of phospholipid flippases, localizes to synapses, and that its expression depends on neuronal activity. Cdc50a knockdown leads to phosphatidylserine exposure at synapses and subsequent erroneous synapse removal by microglia partly via the GPR56 pathway. Taken together, our data support that CDC50A safeguards synapse maintenance by regulating focal phosphatidylserine exposure at synapses.

Neurotransmitter regulation rather than cell-intrinsic properties shape the high-pass filtering properties of olfactory bulb glomeruli

Preprint

Full-text available

Sep 2021

GABAergic periglomerular (PG) cells in the olfactory bulb are proposed to mediate an intraglomerular “high-pass” filter through inhibition targeted onto a glomerulus. With this mechanism, weak stimuli (e.g., an odor with a low affinity for an odorant receptor) mainly produce PG cell-driven inhibition but strong stimuli generate enough excitation to overcome inhibition. PG cells may be particularly susceptible to being activated by weak stimuli due to their intrinsically small size and high input resistance. Here, we used dual-cell patch-clamp recordings and imaging methods in bulb slices obtained from wild-type and transgenic rats with labeled GABAergic cells to test a number of predictions of the high-pass filtering model. We first directly compared the responsiveness of PG cells with that of external tufted cells (eTCs), which are a class of excitatory interneurons that reside in a parallel but opposing position in the glomerular circuitry. PG cells were in fact found to be no more responsive than eTCs at low levels of sensory neuron activity. While PG cells required smaller currents to be excited, this advantage was offset by the fact that a given level of sensory neuron activity produced much smaller synaptic currents. We did however identify other factors that shaped the excitation/inhibition balance in a manner that would support a high-pass filter, including glial glutamate transporters and presynaptic metabotropic glutamate receptors. We conclude that a single glomerulus may act as a high-pass filter to enhance the contrast between different olfactory stimuli through mechanisms that are largely independent cell intrinsic properties. Key Points Summary GABAergic periglomerular (PG) cells in the olfactory bulb are proposed to mediate a “high-pass” filter at a single glomerulus that selectively blocks weak stimulus signals. Their efficacy may reflect their intrinsically small size and high input resistance, which allows them to be easily excited. We found that PG cells were in fact no more likely to be activated by weak stimuli than excitatory neurons. PG cells spiked more readily in response to a fixed current input, but this advantage for excitability was offset by small synaptic currents. Glomeruli nevertheless display an excitation/inhibition balance that can support a high pass filter, becoming much more favorable with increasing stimulus strength. Factors shaping the filter include glial glutamate transporters and presynaptic metabotropic glutamate receptors. We conclude that a single glomerulus may act as a high-pass filter to enhance stimulus contrast through mechanisms that are largely independent of cell-intrinsic properties.

Limited functional convergence of eye-specific inputs in the retinogeniculate pathway of the mouse

Article

Jun 2021
NEURON

Segregation of retinal ganglion cell (RGC) axons by type and eye of origin is considered a hallmark of dorsal lateral geniculate nucleus (dLGN) structure. However, recent anatomical studies have shown that neurons in mouse dLGN receive input from multiple RGC types of both retinae. Whether convergent input leads to relevant functional interactions is unclear. We studied functional eye-specific retinogeniculate convergence using dual-color optogenetics in vitro. dLGN neurons were strongly dominated by input from one eye. Most neurons received detectable input from the non-dominant eye, but this input was weak, with a prominently reduced AMPAR:NMDAR ratio. Consistent with this, only a small fraction of thalamocortical neurons was binocular in vivo across visual stimuli and cortical projection layers. Anatomical overlap between RGC axons and dLGN neuron dendrites alone did not explain the strong bias toward monocularity. We conclude that functional eye-specific input selection and refinement limit convergent interactions in dLGN, favoring monocularity.

Maternal diet during early gestation influences postnatal taste activity–dependent pruning by microglia

Article

Full-text available

Sep 2023
J EXP MED

A key process in central sensory circuit development involves activity-dependent pruning of exuberant terminals. Here, we studied gustatory terminal field maturation in the postnatal mouse nucleus of the solitary tract (NST) during normal development and in mice where their mothers were fed a low NaCl diet for a limited period soon after conception. Pruning of terminal fields of gustatory nerves in controls involved the complement system and is likely driven by NaCl-elicited taste activity. In contrast, offspring of mothers with an early dietary manipulation failed to prune gustatory terminal fields even though peripheral taste activity developed normally. The ability to prune in these mice was rescued by activating myeloid cells postnatally, and conversely, pruning was arrested in controls with the loss of myeloid cell function. The altered pruning and myeloid cell function appear to be programmed before the peripheral gustatory system is assembled and corresponds to the embryonic period when microglia progenitors derived from the yolk sac migrate to and colonize the brain.

β-Catenin and SOX2 Interaction Regulate Visual Experience-Dependent Cell Homeostasis in the Developing Xenopus Thalamus

Article

Full-text available

Sep 2023
INT J MOL SCI

In the vertebrate brain, sensory experience plays a crucial role in shaping thalamocortical connections for visual processing. However, it is still not clear how visual experience influences tissue homeostasis and neurogenesis in the developing thalamus. Here, we reported that the majority of SOX2-positive cells in the thalamus are differentiated neurons that receive visual inputs as early as stage 47 Xenopus. Visual deprivation (VD) for 2 days shifts the neurogenic balance toward proliferation at the expense of differentiation, which is accompanied by a reduction in nuclear-accumulated β-catenin in SOX2-positive neurons. The knockdown of β-catenin decreases the expression of SOX2 and increases the number of progenitor cells. Coimmunoprecipitation studies reveal the evolutionary conservation of strong interactions between β-catenin and SOX2. These findings indicate that β-catenin interacts with SOX2 to maintain homeostatic neurogenesis during thalamus development.

Developmental stage-specific spontaneous activity contributes to callosal axon projections

Article

Full-text available

Aug 2022
eLife

The developing neocortex exhibits spontaneous network activity with various synchrony levels, which has been implicated in the formation of cortical circuits. We previously reported that the development of callosal axon projections, one of the major long-range axonal projections in the brain, is activity dependent. However, what sort of activity and when activity is indispensable are not known. Here, using a genetic method to manipulate network activity in a stage-specific manner, we demonstrated that network activity contributes to callosal axon projections in the mouse visual cortex during a 'critical period': restoring neuronal activity during that period resumed the projections, whereas restoration after the period failed. Furthermore, in vivo Ca2+ imaging revealed that the projections could be established even without fully restoring highly synchronous activity. Overall, our findings suggest that spontaneous network activity is selectively required during a critical developmental time window for the formation of long-range axonal projections in the cortex.

Epigenetic and Transcriptional Regulation of Spontaneous and Sensory Activity Dependent Programs During Neuronal Circuit Development

Article

Full-text available

May 2022

Spontaneous activity generated before the onset of sensory transduction has a key role in wiring developing sensory circuits. From axonal targeting, to synapse formation and elimination, to the balanced integration of neurons into developing circuits, this type of activity is implicated in a variety of cellular processes. However, little is known about its molecular mechanisms of action, especially at the level of genome regulation. Conversely, sensory experience-dependent activity implements well-characterized transcriptional and epigenetic chromatin programs that underlie heterogeneous but specific genomic responses that shape both postnatal circuit development and neuroplasticity in the adult. In this review, we focus on our knowledge of the developmental processes regulated by spontaneous activity and the underlying transcriptional mechanisms. We also review novel findings on how chromatin regulates the specificity and developmental induction of the experience-dependent program, and speculate their relevance for our understanding of how spontaneous activity may act at the genomic level to instruct circuit assembly and prepare developing neurons for sensory-dependent connectivity refinement and processing.

CSMD1 regulates brain complement activity and circuit development

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Mar 2024
BRAIN BEHAV IMMUN

The Dorsal Nucleus of the Lateral Geniculate Body: Anatomy, Histology, Ontogenesis

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Dec 2023

Mapping the Retina onto the Brain

Article

Dec 2023

Vision begins in the retina, which extracts salient features from the environment and encodes them in the spike trains of retinal ganglion cells (RGCs), the output neurons of the eye. RGC axons innervate diverse brain areas (>50 in mice) to support perception, guide behavior, and mediate influences of light on physiology and internal states. In recent years, complete lists of RGC types (∼45 in mice) have been compiled, detailed maps of their dendritic connections drawn, and their light responses surveyed at scale. We know less about the RGCs' axonal projection patterns, which map retinal information onto the brain. However, some organizing principles have emerged. Here, we review the strategies and mechanisms that govern developing RGC axons and organize their innervation of retinorecipient brain areas.

Activity-dependent development of the body's touch receptors

Preprint

Full-text available

Sep 2023

We report a role for activity in the development of the primary sensory neurons that detect touch. Genetic deletion of Piezo2, the principal mechanosensitive ion channel in somatosensory neurons, caused profound changes in the formation of mechanosensory end organ structures and altered somatosensory neuron central targeting. Single cell RNA sequencing of Piezo2 conditional mutants revealed changes in gene expression in the sensory neurons activated by light mechanical forces, whereas other neuronal classes were less affected. To further test the role of activity in mechanosensory end organ development, we genetically deleted the voltage-gated sodium channel Nav1.6 (Scn8a) in somatosensory neurons throughout development and found that Scn8a mutants also have disrupted somatosensory neuron morphologies and altered electrophysiological responses to mechanical stimuli. Together, these findings indicate that mechanically evoked neuronal activity acts early in life to shape the maturation of the mechanosensory end organs that underlie our sense of gentle touch.

A short period of early life oxytocin treatment rescues social behavior dysfunction via suppression of hippocampal hyperactivity in male mice

Article

Full-text available

Jul 2022

Early sensory experiences interact with genes to shape precise neural circuits during development. This process is vital for proper brain function in adulthood. Neurological dysfunctions caused by environmental alterations and/or genetic mutation may share the same molecular or cellular mechanisms. Here, we show that early life bilateral whisker trimming (BWT) subsequently affects social discrimination in adult male mice. Enhanced activation of the hippocampal dorsal CA3 (dCA3) in BWT mice was observed during social preference tests. Optogenetic activation of dCA3 in naive mice impaired social discrimination, whereas chemogenetic silencing of dCA3 rescued social discrimination deficit in BWT mice. Hippocampal oxytocin (OXT) is reduced after whisker trimming. Neonatal intraventricular compensation of OXT relieved dCA3 over-activation and prevented social dysfunction. Neonatal knockdown of OXT receptor in dCA3 mimics the effects of BWT, and cannot be rescued by OXT treatment. Social behavior deficits in a fragile X syndrome mouse model (Fmr1 KO mice) could also be recovered by early life OXT treatment, through negating dCA3 over-activation. Here, a possible avenue to prevent social dysfunction is uncovered.

CKAMP44 controls synaptic function and strength of relay neurons during early development of the dorsal lateral geniculate nucleus

Article

Full-text available

Jul 2022
J PHYSIOL-LONDON

Relay neurons of the dorsal lateral geniculate nucleus (dLGN) receive inputs from retinal ganglion cells via retinogeniculate synapses. These connections undergo pruning in the first 2 weeks after eye opening. The remaining connections are strengthened several‐fold by the insertion of AMPA receptors (AMPARs) into weak or silent synapses. In this study, we found that the AMPAR auxiliary subunit CKAMP44 is required for receptor insertion and function of retinogeniculate synapses during development. Genetic deletion of CKAMP44 resulted in decreased synaptic strength and a higher number of silent synapses in young (P9–11) mice. Recovery from desensitisation of AMPARs was faster in CKAMP44 knockout (CKAMP44–/–) than in wild‐type mice. Moreover, loss of CKAMP44 increased the probability of inducing plateau potentials, which are known to be important for eye‐specific input segregation and retinogeniculate synapse maturation. The anatomy of relay neurons in the dLGN was changed in young CKAMP44–/– mice showing a transient increase in dendritic branching that normalised during later development (P26–33). Interestingly, input segregation in young CKAMP44–/– mice was not affected when compared to wild‐type mice. These results demonstrate that CKAMP44 promotes maturation and modulates function of retinogeniculate synapses during early development of the visual system without affecting input segregation. image Key points Expression of CKAMP44 starts early during development of the dorsal lateral geniculate nucleus (dLGN) and remains stable in relay neurons and interneurons. Genetic deletion of CKAMP44 decreases synaptic strength and increases silent synapse number in dLGN relay neurons; increases the rate of recovery from desensitisation of AMPA receptors in dLGN relay neurons; and reduces synaptic short‐term depression in retinogeniculate synapses. The probability of inducing plateau potentials is elevated in relay neurons of CKAMP44–/– mice. Eye‐specific input segregation is unaffected in the dLGN of CKAMP44–/– mice. Deletion of CKAMP44 mildly affects dendritic arborisation of relay neurons in the dLGN.

Adenosine A 2A receptor modulates microglia-mediated synaptic pruning of the retinogeniculate pathway during postnatal development

Preprint

Full-text available

Jan 2021

Synapse pruning is essential not only for the developmental establishment of synaptic connections in the brain but also for the pathogenesis of neurodevelopmental and neurodegenerative disorders. However, there are no effective pharmacological means to regulate synaptic pruning during early development. Using the eye-specific segregation of the dorsal lateral geniculate nucleus (dLGN) as a model of synaptic pruning coupled with aden-osine A 2A receptor (A 2A R) antagonism and knockout, we demonstrated while genetic deletion of the A 2A R throughout the development attenuated eye-specific segregation with the attenuated microglial phagocytosis at postnatal day 5 (P5), selective treatment with the A 2A R antagonist KW6002 at P2-P4 facilitated synaptic pruning of visual pathway with microglial activation, increased lysosomal activity in microglia and increased microglial engulfment of retinal ganglion cell (RGC) inputs in the dLGN at P5 (but not P10). Furthermore, KW6002-mediated facilitation of synaptic pruning was activity-dependent since tetrodotoxin (TTX) treatment abolished the KW6002 facilitation. Moreover, the A 2A R antagonist also modulated postsynaptic proteins and synaptic density at early postnatal stages as revealed by the reduced immunoreactivity of postsynaptic proteins (Homer1 and metabotropic glutamate receptor 5) and colocalization of presynaptic VGlut2 and postsynaptic Homer1 puncta in the dLGN. These findings suggest that A 2A R can control pruning by multiple actions involving the retinal wave, microglia engulfment, and postsynaptic stability. Thus, A 2A R antagonists may represent a novel pharmacological strategy to modulate microglia-mediated synaptic pruning and treatment of neuro-developmental disorders associated with dysfunctional pruning.

Structural and Functional Plasticity in the Dorsolateral Geniculate Nucleus of Mice following Bilateral Enucleation

Article

Full-text available

Feb 2022
NEUROSCIENCE

Within the nervous system, plasticity mechanisms attempt to stabilize network activity following disruption by injury, disease, or degeneration. Optic nerve injury and age-related diseases can induce homeostatic-like responses in adulthood. We tested this possibility in the thalamocortical (TC) neurons in the dorsolateral geniculate nucleus (dLGN) using patch-clamp electrophysiology, optogenetics, immunostaining, and single-cell dendritic analysis following loss of visual input via bilateral enucleation. We observed progressive loss of vGlut2-positive retinal terminals in the dLGN indicating degeneration post-enucleation that was coincident with changes in microglial morphology indicative of microglial activation. Consistent with the decline of vGlut2 puncta, we also observed loss of retinogeniculate (RG) synaptic function assessed using optogenetic activation of RG axons while performing whole-cell voltage clamp recordings from TC neurons in brain slices. Surprisingly, we did not detect any significant changes in the frequency of miniature post-synaptic currents (mEPSCs) or corticothalamic feedback synapses. Analysis of TC neuron dendritic structure from single-cell dye fills revealed a gradual loss of dendrites proximal to the soma, where TC neurons receive the bulk of RG inputs. Finally, analysis of action potential firing demonstrated that TC neurons have increased excitability following enucleation, firing more action potentials in response to depolarizing current injections. Our findings show that degeneration of the retinal axons/optic nerve and loss of RG synaptic inputs induces structural and functional changes in TC neurons, consistent with neuronal attempts at compensatory plasticity in the dLGN.

Retinal waves align the concentric orientation map in mouse superior colliculus to the center of vision

Preprint

Jan 2022

Neurons in the mouse superior colliculus (SC) are arranged in an orientation preference map that has a concentric organization, which is aligned to the center of vision and the optic flow experienced by the mouse. The developmental mechanisms that underlie this functional map remain unclear. Here, we propose that the spatiotemporal properties of spontaneous retinal waves during development provide a scaffold to establish the concentric orientation map in the mouse SC and its alignment to the optic flow. We test this hypothesis by modelling the orientation-tuned SC neurons that receive ON/OFF retinal inputs. Our results suggest that the stage III retinal wave properties, namely OFF delayed response and the wave propagation direction bias, are key factors that regulate the spatial organization of the SC orientation map. Specifically, the OFF delay mediates the establishment of orientation-tuned SC neurons by segregating their ON/OFF receptive subfields, the wave-like activities facilitate the formation of a concentric pattern, and the wave direction biases align the orientation map to the center of vision. Taken together, our model suggests that retinal waves may play an instructive role in establishing functional properties of SC neurons and provides a promising mechanism for explaining the correlations between the optic flow and the SC orientation map.

Development of astrocyte morphology and function in mouse visual thalamus

Article

Oct 2021

The rodent visual thalamus has served as a powerful model to elucidate the cellular and molecular mechanisms that underlie sensory circuit formation and function. Despite significant advances in our understanding of the role of axon-target interactions and neural activity in orchestrating circuit formation in visual thalamus, the role of non-neuronal cells, such as astrocytes, is less clear. In fact, we know little about the transcriptional identity and development of astrocytes in mouse visual thalamus. To address this gap in knowledge, we studied the expression of canonical astrocyte molecules in visual thalamus using immunostaining, in situ hybridization, and reporter lines. While our data suggests some level of heterogeneity of astrocytes in different nuclei of the visual thalamus, the majority of thalamic astrocytes appeared to be labelled in Aldh1l1-EGFP mice. This led us to use this transgenic line to characterize the neonatal and postnatal development of these cells in visual thalamus. Our data show that not only have the entire cohort of astrocytes migrated into visual thalamus by eye-opening but they also have acquired their adult-like morphology, even while retinogeniculate synapses are still maturing. Furthermore, ultrastructural, immunohistochemical, and functional approaches revealed that by eye-opening, thalamic astrocytes ensheath retinogeniculate synapses and are capable of efficient uptake of glutamate. Taken together, our results reveal that the morphological, anatomical, and functional development of astrocytes in visual thalamus occurs prior to eye-opening and the emergence of experience-dependent visual activity. This article is protected by copyright. All rights reserved

Adenosine A2A receptor modulates microglia-mediated synaptic pruning of the retinogeniculate pathway during postnatal development

Article

Sep 2021
NEUROPHARMACOLOGY

Synapse pruning is essential not only for the developmental establishment of synaptic connection in the brain but also for the pathogenesis of neurodevelopmental and neurodegenerative disorders. However, there are no effective pharmacological means to regulate synaptic pruning during early development. Using the eye-specific segregation of the dorsal lateral geniculate nucleus (dLGN) as a model of synaptic pruning coupled with adenosine A2A receptor (A2AR) antagonism and knockout, we demonstrated while genetic deletion of the A2AR throughout the development attenuated eye segregation with the attenuated microglial phagocytosis at postnatal day 5 (P5), selective treatment with the A2AR antagonist KW6002 at P2-P4 facilitated synaptic pruning of visual pathway with microglial activation, increased lysosomal activity in microglia and increased microglial engulfment of retinal ganglion cell (RGC) inputs in the dLGN at P5 (but not P10). Furthermore, KW6002-mediated facilitation of synaptic pruning was activity-dependent since tetrodotoxin (TTX) treatment abolished the KW6002 facilitation. Moreover, the A2AR antagonist also modulated postsynaptic proteins and synaptic density at early postnatal stages as revealed by the reduced immunoreactivity of postsynaptic proteins (Homer1 and metabotropic glutamate receptor 5) and colocalization of presynaptic VGlut2 and postsynaptic Homer1 puncta in the dLGN. These findings suggest that A2AR can control pruning by multiple actions involving the retinal wave, microglia engulfment, and postsynaptic stability. Thus, A2AR antagonists may represent a novel pharmacological strategy to modulate microglia-mediated synaptic pruning and treatment of neurodevelopmental disorders associated with dysfunctional pruning.

Single-cell and single-nucleus RNA-seq uncovers shared and distinct axes of variation in dorsal LGN neurons in mice, non-human primates, and humans

Article

Full-text available

Sep 2021
eLife

Abundant evidence supports the presence of at least three distinct types of thalamocortical (TC) neurons in the primate dorsal lateral geniculate nucleus (dLGN) of the thalamus, the brain region that conveys visual information from the retina to the primary visual cortex (V1). Different types of TC neurons in mice, humans, and macaques have distinct morphologies, distinct connectivity patterns, and convey different aspects of visual information to the cortex. To investigate the molecular underpinnings of these cell types, and how these relate to differences in dLGN between human, macaque, and mice, we profiled gene expression in single nuclei and cells using RNA-sequencing. These efforts identified four distinct types of TC neurons in the primate dLGN: magnocellular (M) neurons, parvocellular (P) neurons, and two types of koniocellular (K) neurons. Despite extensively documented morphological and physiological differences between M and P neurons, we identified few genes with significant differential expression between transcriptomic cell types corresponding to these two neuronal populations. Likewise, the dominant feature of TC neurons of the adult mouse dLGN is high transcriptomic similarity, with an axis of heterogeneity that aligns with core vs. shell portions of mouse dLGN. Together, these data show that transcriptomic differences between principal cell types in the mature mammalian dLGN are subtle relative to the observed differences in morphology and cortical projection targets. Finally, alignment of transcriptome profiles across species highlights expanded diversity of GABAergic neurons in primate versus mouse dLGN and homologous types of TC neurons in primates that are distinct from TC neurons in mouse.

Microglia, Cytokines, and Neural Activity: Unexpected Interactions in Brain Development and Function

Article

Full-text available

Jul 2021

Intercellular signaling molecules such as cytokines and their receptors enable immune cells to communicate with one another and their surrounding microenvironments. Emerging evidence suggests that the same signaling pathways that regulate inflammatory responses to injury and disease outside of the brain also play powerful roles in brain development, plasticity, and function. These observations raise the question of how the same signaling molecules can play such distinct roles in peripheral tissues compared to the central nervous system, a system previously thought to be largely protected from inflammatory signaling. Here, we review evidence that the specialized roles of immune signaling molecules such as cytokines in the brain are to a large extent shaped by neural activity, a key feature of the brain that reflects active communication between neurons at synapses. We discuss the known mechanisms through which microglia, the resident immune cells of the brain, respond to increases and decreases in activity by engaging classical inflammatory signaling cascades to assemble, remodel, and eliminate synapses across the lifespan. We integrate evidence from (1) in vivo imaging studies of microglia-neuron interactions, (2) developmental studies across multiple neural circuits, and (3) molecular studies of activity-dependent gene expression in microglia and neurons to highlight the specific roles of activity in defining immune pathway function in the brain. Given that the repurposing of signaling pathways across different tissues may be an important evolutionary strategy to overcome the limited size of the genome, understanding how cytokine function is established and maintained in the brain could lead to key insights into neurological health and disease.

THE DORSAL LATERAL GENICULATE NUCLEUS: ANATOMY, HISTOLOGY, ONTOGENESIS

Article

May 2023
ZH VYSSH NERV DEYAT+

Review is devoted to the structure and function of the main visual thalamic nucleus – dorsal part of the lateral geniculate nucleus, and its formation during prenatal and postnatal ontogenesis. The structure and ontogeny of the related structures (retinal ganglion cells and visual cortex, and their projections) are also reviewed. Particular attention is paid to the morphological and functional differences between X, Y, and W parallel channels, and to the development of different layers of the dorsal the lateral geniculate nucleus.

Sleep regulation and host genetics

Chapter

Jan 2024

An early enriched experience drives targeted microglial engulfment of miswired neural circuitry during a restricted postnatal period

Article

Mar 2024
GLIA

Brain function is critically dependent on correct circuit assembly. Microglia are well‐known for their important roles in immunological defense and neural plasticity, but whether they can also mediate experience‐induced correction of miswired circuitry is unclear. Ten‐m3 knockout (KO) mice display a pronounced and stereotyped visuotopic mismapping of ipsilateral retinal inputs in their visual thalamus, providing a useful model to probe circuit correction mechanisms. Environmental enrichment (EE) commenced around birth, but not later in life, can drive a partial correction of the most mismapped retinal inputs in Ten‐m3 KO mice. Here, we assess whether enrichment unlocks the capacity for microglia to selectively engulf and remove miswired circuitry, and the timing of this effect. Expression of the microglial‐associated lysosomal protein CD68 showed a clear enrichment‐driven, spatially restricted change which had not commenced at postnatal day (P)18, was evident at P21, more robust at P25, and had ceased by P30. This was observed specifically at the corrective pruning site and was absent at a control site. An engulfment assay at the corrective pruning site in P25 mice showed EE‐driven microglial‐uptake of the mismapped axon terminals. This was temporally and spatially specific, as no enrichment‐driven microglial engulfment was seen in P18 KO mice, nor the control locus. The timecourse of the EE‐driven corrective pruning as determined anatomically, aligned with this pattern of microglia reactivity and engulfment. Collectively, these findings show experience can drive targeted microglial engulfment of miswired neural circuitry during a restricted postnatal window. This may have important therapeutic implications for neurodevelopmental conditions involving aberrant neural connectivity.

A developmental critical period for ocular dominance plasticity of binocular neurons in mouse superior colliculus

Article

Jan 2024

Molecular mechanisms underlying microglial sensing and phagocytosis in synaptic pruning

Article

Sep 2023

Microglia are the main non-neuronal cells in the central nervous system that have important roles in brain development and functional connectivity of neural circuits. In brain physiology, highly dynamic microglial processes are facilitated to sense the surrounding environment and stimuli. Once the brain switches its functional states, microglia are recruited to specific sites to exert their immune functions, including the release of cytokines and phagocytosis of cellular debris. The crosstalk of microglia between neurons, neural stem cells, endothelial cells, oligodendrocytes, and astrocytes contributes to their functions in synapse pruning, neurogenesis, vascularization, myelination, and blood-brain barrier permeability. In this review, we highlight the neuron-derived “find-me,” “eat-me,” and “don’t eat-me” molecular signals that drive microglia in response to changes in neuronal activity for synapse refinement during brain development. This review reveals the molecular mechanism of neuron-microglia interaction in synaptic pruning and presents novel ideas for the synaptic pruning of microglia in disease, thereby providing important clues for discovery of target drugs and development of nervous system disease treatment methods targeting synaptic dysfunction.

Retinal waves align the concentric orientation map in mouse superior colliculus to the center of vision

Article

May 2023

Neurons in the mouse superior colliculus (SC) are arranged in a concentric orientation map, which is aligned to the center of vision and the optic flow experienced by the mouse. The origin of this map remains unclear. Here, we propose that spontaneous retinal waves during development provide a scaffold to establish the concentric orientation map within the SC and its alignment to the optic flow. We test this hypothesis by modeling the orientation-tuned SC neurons that receive ON/OFF retinal inputs. Our model suggests that the propagation direction bias of stage III retinal waves, together with OFF-delayed responses, shapes the spatial organization of the orientation map. The OFF delay establishes orientation-tuned neurons by segregating their ON/OFF receptive subfields, the wave-like activities form the concentric pattern, and the direction biases align the map to the center of vision. Together, retinal waves may play an instructive role in establishing functional properties of single SC neurons and their spatial organization within maps.

Activity-Dependent Synapse Refinement: From Mechanisms to Molecules

Article

May 2023
NEUROSCIENTIST

The refinement of immature neuronal networks into efficient mature ones is critical to nervous system development and function. This process of synapse refinement is driven by the neuronal activity-dependent competition of converging synaptic inputs, resulting in the elimination of weak inputs and the stabilization of strong ones. Neuronal activity, whether in the form of spontaneous activity or experience-evoked activity, is known to drive synapse refinement in numerous brain regions. More recent studies are now revealing the manner and mechanisms by which neuronal activity is detected and converted into molecular signals that appropriately regulate the elimination of weaker synapses and stabilization of stronger ones. Here, we highlight how spontaneous activity and evoked activity instruct neuronal activity-dependent competition during synapse refinement. We then focus on how neuronal activity is transformed into the molecular cues that determine and execute synapse refinement. A comprehensive understanding of the mechanisms underlying synapse refinement can lead to novel therapeutic strategies in neuropsychiatric diseases characterized by aberrant synaptic function.

Synaptogenesis

Chapter

Feb 2023

The development of cognitive, sensory, and motor function depends on the formation of specific synaptic connections. Not only must synapses form among appropriate partners, but they also must acquire the appropriate properties to serve their particular functions in the circuit. The establishment of mature neuronal connectivity depends on coordinated activity of many individual molecules, any of which could potentially be altered by genetic variation and mutation. This chapter will provide an overview of the structure and molecular composition of synapses of the central nervous system (CNS). We will then discuss how the precise and intricate connectivity of the CNS is established through formation and selective elimination of chemical synapses, and how perturbation of these processes may result in neurodevelopmental disease.

Structural and functional integration of human forebrain organoids with the injured adult rat visual system

Article

Feb 2023
CELL STEM CELL

Brain organoids created from human pluripotent stem cells represent a promising approach for brain repair. They acquire many structural features of the brain and raise the possibility of patient-matched repair. Whether these entities can integrate with host brain networks in the context of the injured adult mammalian brain is not well established. Here, we provide structural and functional evidence that human brain organoids successfully integrate with the adult rat visual system after transplantation into large injury cavities in the visual cortex. Virus-based trans-synaptic tracing reveals a polysynaptic pathway between organoid neurons and the host retina and reciprocal connectivity between the graft and other regions of the visual system. Visual stimulation of host animals elicits responses in organoid neurons, including orientation selectivity. These results demonstrate the ability of human brain organoids to adopt sophisticated function after insertion into large injury cavities, suggesting a translational strategy to restore function after cortical damage.

Brainstem serotonin neurons selectively gate retinal information flow to thalamus

Article

Dec 2022

Retinal ganglion cell (RGC) types relay parallel streams of visual feature information. We hypothesized that neuromodulators might efficiently control which visual information streams reach the cortex by selectively gating transmission from specific RGC axons in the thalamus. Using fiber photometry recordings, we found that optogenetic stimulation of serotonergic axons in primary visual thalamus of awake mice suppressed ongoing and visually evoked calcium activity and glutamate release from RGC boutons. Two-photon calcium imaging revealed that serotonin axon stimulation suppressed RGC boutons that responded strongly to global changes in luminance more than those responding only to local visual stimuli, while the converse was true for suppression induced by increases in arousal. Converging evidence suggests that differential expression of the 5-HT1B receptor on RGC presynaptic terminals, but not differential density of nearby serotonin axons, may contribute to the selective serotonergic gating of specific visual information streams before they can activate thalamocortical neurons.

Loss of Retinogeniculate Synaptic Function in the DBA/2J Mouse Model of Glaucoma

Article

Full-text available

Dec 2022

Retinal ganglion cell (RGC) axons comprise the optic nerve and carry information to the dorsolateral geniculate nucleus (dLGN), which is then relayed to the cortex for conscious vision. Glaucoma is a blinding neurodegenerative disease that commonly results from intraocular pressure (IOP)-associated injury leading to RGC axonal pathology, disruption of RGC outputs to the brain, and eventual apoptotic loss of RGC somata. The consequences of elevated IOP and glaucomatous pathology on RGC signaling to the dLGN are largely unknown yet are likely to contribute to vision loss. Here, we used anatomic and physiological approaches to study the structure and function of retinogeniculate (RG) synapses in male and female DBA/2J (D2) mice with inherited glaucoma before and after IOP elevation. D2 mice showed progressive loss of anterograde optic tract transport to the dLGN and vGlut2 labeling of RGC axon terminals while patch-clamp measurements of RG synaptic function showed that synaptic transmission was reduced in 9-month and 12-month D2 mice because of the loss of individual RGC axon inputs. TC neuron dendrites had reduced Sholl complexity at 12 months, suggestive of delayed reorganization following reduced synaptic input. There was no detectable change in RGC density in 11- to 12-month D2 retinas, quantified as the number of ganglion cell layer-residing somata immuno-positive for NeuN and immuno-negative for the amacrine marker choline acetyltransferase (ChAT). Thus, observed synaptic defects appear to precede RGC somatic loss. These findings identify glaucoma-associated and IOP-associated deficits in an important subcortical RGC projection target, shedding light on processes linking IOP to vision loss.

An Early Enriched Experience Drives an Activated Microglial Profile at Site of Corrective Neuroplasticity in Ten-m3 Knock-Out Mice

Article

Full-text available

Dec 2022

Environmental enrichment (EE) is beneficial for brain development and function, but our understanding of its capacity to drive circuit repair, the underlying mechanisms, and how this might vary with age remains limited. Ten-m3 knock-out (KO) mice exhibit a dramatic and stereotyped mistargeting of ipsilateral retinal inputs to the thalamus, resulting in visual deficits. We have recently shown a previously unexpected capacity for EE during early postnatal life (from birth for six weeks) to drive the partial elimination of miswired axonal projections, along with a recovery of visually mediated behavior, but the timeline of this repair was unclear. Here, we reveal that with just 3.5 weeks of EE from birth, Ten-m3 KOs exhibit a partial behavioral rescue, accompanied by pruning of the most profoundly miswired retinogeniculate terminals. Analysis suggests that the pruning is underway at this time point, providing an ideal opportunity to probe potential mechanisms. With the shorter EE-period, we found a localized increase in microglial density and activation profile within the identified geniculate region where corrective pruning was observed. No comparable response to EE was found in age-matched wild-type (WT) mice. These findings identify microglia as a potential mechanistic link through which EE drives the elimination of miswired neural circuits during early postnatal development. Activity driven, atypical recruitment of microglia to prune aberrant connectivity and restore function may have important therapeutic implications for neurodevelopmental disorders such as autistic spectrum disorder.

The encoding of touch by somatotopically aligned dorsal column subdivisions

Article

Full-text available

Nov 2022
NATURE

The somatosensory system decodes a range of tactile stimuli to generate a coherent sense of touch. Discriminative touch of the body depends on signals conveyed from peripheral mechanoreceptors to the brain through the spinal cord dorsal column and its brainstem target, the dorsal column nuclei (DCN)1,2. Models of somatosensation emphasize that fast-conducting low-threshold mechanoreceptors (LTMRs) innervating the skin drive the DCN3,4. However, postsynaptic dorsal column (PSDC) neurons within the spinal cord dorsal horn also collect mechanoreceptor signals and form a second major input to the DCN5–7. The significance of PSDC neurons and their contributions to the coding of touch have remained unclear since their discovery. Here we show that direct LTMR input to the DCN conveys vibrotactile stimuli with high temporal precision. Conversely, PSDC neurons primarily encode touch onset and the intensity of sustained contact into the high-force range. LTMR and PSDC signals topographically realign in the DCN to preserve precise spatial detail. Different DCN neuron subtypes have specialized responses that are generated by distinct combinations of LTMR and PSDC inputs. Thus, LTMR and PSDC subdivisions of the dorsal column encode different tactile features and differentially converge in the DCN to generate specific ascending sensory processing streams.

Preface to the Second Edition

Chapter

Jan 2010

New Haven Stockholm

Development of the brain and the emergence of the mind constitute some of the most important concerns of contemporary biology. Disturbances during fetal life may have profound implications for a child's future neurological and psychological development, which can in turn impact society. The new edition of this highly respected work presents a comprehensive review of the basic mechanisms of brain development and the pathophysiology of disorders of the infant brain, written by a team of distinguished neuroscientists, neonatologists, and neuropediatricians. The book follows the main milestones of brain development, from formation of the neural tube and wiring of the neurons in the brain. Neurotrophic factors, neurotransmitters, glial cell biology, cerebral circulation development of sensory functions are all described in detail. Furthermore, there are more philosophical chapters on the evolution of the brain and the emergence of consciousness. Clinical considerations are highlighted where relevant.

Neurotransmitters and neuromodulators

Chapter

Jan 2010

Neurotrophic factors in brain development

Chapter

Jan 2010

Thomas Ringstedt

The encoding of touch by somatotopically aligned dorsal column subdivisions

Preprint

Aug 2022

The somatosensory system decodes a range of tactile stimuli to generate a coherent sense of touch. Discriminative touch of the body depends on signals conveyed from peripheral mechanoreceptors to the brain via the spinal cord dorsal column and its brainstem target the dorsal column nuclei (DCN) 1, 2 . Models of somatosensation emphasize that fast-conducting low- threshold mechanoreceptors (LTMRs) innervating the skin drive the DCN 3, 4 . However, post- synaptic dorsal column neurons (PSDCs) within the spinal cord dorsal horn also collect mechanoreceptor signals and form a second major input to the DCN 5–7 . The significance of PSDCs and their contributions to the coding of touch have remained unclear since their discovery. Here, we show that direct LTMR inputs to the DCN convey vibrotactile stimuli with high temporal precision, whereas PSDCs primarily encode touch onset and the intensity of sustained contact into the high force range. LTMR and PSDC signals topographically re-align in the DCN to preserve precise spatial detail. Different DCN neuron subtypes have specialized responses that are generated by unique combinations of LTMR and PSDC inputs. Thus, LTMR and PSDC subdivisions of the dorsal column encode different tactile features and differentially converge in the DCN to generate unique ascending sensory processing streams.

A Guide for the Multiplexed: The Development of Visual Feature Maps in the Brain

Article

Aug 2022
NEUROSCIENCE

Neural maps are found ubiquitously in the brain, where they encode a wide range of behaviourally relevant features into neural space. Developmental studies have shown that animals devote a great deal of resources to establish consistently patterned organization in neural circuits throughout the nervous system, but what purposes maps serve beneath their often intricate appearance and composition is a topic of active debate and exploration. In this article, we review the general mechanisms of map formation, with a focus on the visual system, and then survey notable organizational properties of neural maps: the multiplexing of feature representations through a nested architecture, the interspersing of fine-scale heterogeneity within a globally smooth organization, and the complex integration at the microcircuit level that enables a high dimensionality of information encoding. Finally, we discuss the roles of maps in cortical functions, including input segregation, feature extraction and routing of circuit outputs for higher order processing, as well as the evolutionary basis for the properties we observe in neural maps.

Vision-Dependent and -Independent Molecular Maturation of Mouse Retinal Ganglion Cells

Article

Jul 2022
NEUROSCIENCE

The development and connectivity of retinal ganglion cells (RGCs), the retina’s sole output neurons, are patterned by activity-independent transcriptional programs and activity-dependent remodeling. To inventory the molecular correlates of these influences, we applied high-throughput single-cell RNA sequencing (scRNA-seq) to mouse RGCs at six embryonic and postnatal ages. We identified temporally regulated modules of genes that correlate with, and likely regulate, multiple phases of RGC development, ranging from differentiation and axon guidance to synaptic recognition and refinement. Some of these genes are expressed broadly while others, including key transcription factors and recognition molecules, are selectively expressed by one or a few of the 45 transcriptomically distinct types defined previously in adult mice. Next, we used these results as a foundation to analyze the transcriptomes of RGCs in mice lacking visual experience due to dark rearing from birth or to mutations that ablate either bipolar or photoreceptor cells. 98.5% of visually deprived (VD) RGCs could be unequivocally assigned to a single RGC type based on their transcriptional profiles, demonstrating that visual activity is dispensable for acquisition and maintenance of RGC type identity. However, visual deprivation significantly reduced the transcriptomic distinctions among RGC types, implying that activity is required for complete RGC maturation or maintenance. Consistent with this notion, transcriptomic alternations in VD RGCs significantly overlapped with gene modules found in developing RGCs. Our results provide a resource for mechanistic analyses of RGC differentiation and maturation, and for investigating the role of activity in these processes.

Functional convergence of on-off direction-selective ganglion cells in the visual thalamus

Article

Jun 2022

In the mouse visual system, multiple types of retinal ganglion cells (RGCs) each encode distinct features of the visual space. A clear understanding of how this information is parsed in their downstream target, the dorsal lateral geniculate nucleus (dLGN), remains elusive. Here, we characterized retinogeniculate connectivity in Cart-IRES2-Cre-D and BD-CreER2 mice, which labels subsets of on-off direction-selective ganglion cells (ooDSGCs) tuned to the vertical directions and to only ventral motion, respectively. Our immunohistochemical, electrophysiological, and optogenetic experiments reveal that only a small fraction (<15%) of thalamocortical (TC) neurons in the dLGN receives primary retinal drive from these subtypes of ooDSGCs. The majority of the functionally identifiable ooDSGC inputs in the dLGN are weak and converge together with inputs from other RGC types. Yet our modeling indicates that this mixing is not random: BD-CreER+ ooDSGC inputs converge less frequently with ooDSGCs tuned to the opposite direction than with non-CART-Cre+ RGC types. Taken together, these results indicate that convergence of distinct information lines in dLGN follows specific rules of organization.

Pathway-specific maturation of presynaptic functions of the somatosensory thalamus

Article

May 2022
NEUROSCI RES

Mitsuharu Midorikawa

Neural circuits are the bases of brain function, and signal transmission between neurons is mediated by synapses. However, neural circuits and synapses are not fully functional at the time of birth. In the nervous system of newborn animals, neurons form an extensive number of redundant synapses that are targeted to construct neural circuits, of which 40–50% are subsequently eliminated during adolescence before circuit maturation. It is widely understood that the maturation of synaptic function differs between surviving and eliminated synapses before their eventual selection; however, direct evidence is currently lacking because of technical limitations. We recently acquired direct electrical recordings from single synapses destined for survival and elimination in the rodent somatosensory thalamus. Results demonstrated detailed presynaptic functional development both in surviving and eliminated pathways. Our work not only revealed the functional properties of surviving and eliminated synapses but also provided a new model system to elucidate the mechanisms that underlie mature neural circuit formation.

Development and experience-dependent modulation of the defensive behaviors of mice to visual threats

Article

Full-text available

Dec 2022

Rodents demonstrate defensive behaviors such as fleeing or freezing upon recognizing a looming shadow above them. Although individuals’ experiences in their habitat can modulate the defensive behavior phenotype, the effects of systematically manipulating the individual’s visual experience on vision-guided defensive behaviors have not been studied. We aimed to describe the developmental process of defensive behaviors in response to visual threats and the effects of visual deprivation. We found that the probability of escape response occurrence increased 3 weeks postnatally, and then stabilized. When visual experience was perturbed by dark rearing from postnatal day (P) 21 for a week, the developmental increase in escape probability was clearly suppressed, while the freezing probability increased. Intriguingly, exposure to the looming stimuli at P28 reversed the suppression of escape response development at P35. These results clearly indicate that the development of defensive behaviors in response to looming stimuli is affected by an individual’s sensory experience.

Development of Functional Properties in the Early Visual System: New Appreciations of the Roles of Lateral Geniculate Nucleus

Chapter

Feb 2022

In the years following Hubel and Wiesel’s first reports on ocular dominance plasticity and amblyopia, much attention has been focused on understanding the role of cortical circuits in developmental and experience-dependent plasticity. Initial studies found few differences between retinal ganglion cells and neurons in the lateral geniculate nucleus and uncovered little evidence for an impact of altered visual experience on the functional properties of lateral geniculate nucleus neurons. In the last two decades, however, studies have revealed that the connectivity between the retina and lateral geniculate nucleus is much richer than was previously appreciated, even revealing visual plasticity – including ocular dominance plasticity – in lateral geniculate nucleus neurons. Here we review the development of the early visual system and the impact of experience with a distinct focus on recent discoveries about lateral geniculate nucleus, its connectivity, and evidence for its plasticity and rigidity during development.

Activity-dependent modulation of synapse-regulating genes in astrocytes

Article

Full-text available

Sep 2021
eLife

Astrocytes regulate the formation and function of neuronal synapses via multiple signals, however, what controls regional and temporal expression of these signals during development is unknown. We determined the expression profile of astrocyte synapse-regulating genes in the developing mouse visual cortex, identifying astrocyte signals that show differential temporal and layer-enriched expression. These patterns are not intrinsic to astrocytes, but regulated by visually-evoked neuronal activity, as they are absent in mice lacking glutamate release from thalamocortical terminals. Consequently, synapses remain immature. Expression of synapse-regulating genes and synaptic development are also altered when astrocyte signaling is blunted by diminishing calcium release from astrocyte stores. Single nucleus RNA sequencing identified groups of astrocytic genes regulated by neuronal and astrocyte activity, and a cassette of genes that show layer-specific enrichment. Thus, the development of cortical circuits requires coordinated signaling between astrocytes and neurons, highlighting astrocytes as a target to manipulate in neurodevelopmental disorders.

An activity-dependent determinant of synapse elimination in the mammalian brain

Article

Mar 2021
NEURON

To establish functional neural circuits in the brain, synaptic connections are refined by neural activity during development, where active connections are maintained and inactive ones are eliminated. However, the molecular signals that regulate synapse refinement remain to be elucidated. When we inactivate a subset of neurons in the mouse cingulate cortex, their callosal connections are eliminated through activity-dependent competition. Using this system, we identify JAK2 tyrosine kinase as a key regulator of inactive synapse elimination. We show that JAK2 is necessary and sufficient for elimination of inactive connections; JAK2 is activated at inactive synapses in response to signals from other active synapses; STAT1, a substrate of JAK2, mediates inactive synapse elimination; JAK2 signaling is critical for physiological refinement of synapses during normal development; and JAK2 regulates synapse refinement in multiple brain regions. We propose that JAK2 is an activity-dependent switch that serves as a determinant of inactive synapse elimination.

Evidence for a multiple innervation of Purkinje cells by climbing fibers in the immature rat cerebellum

Article

Full-text available

Nov 1976

Climbing fiber (CF)-Purkinje cell (PC) relationship were studied electrophysiologically on the cerebellum of 8 to 15 day old rats. Some animals were rendered agranular by x-irradiation from birth; some others were treated with 3-acetyl pyridine 3 days before study to selectively destroy the CF. Unitary extracellular recordings in 8-9 day old normal rats revealed that more than 50% of the PC units each exhibited either two types of all-or-none climbing fiber responses (CFR) or stepwise graded CFRs. The other PC units only presented one type of all-or-none CFR. These activities were entirely mediated via CF since they persisted at the same age in x-irradiated rats, but were absent in animals treated with 3-acetyl pyridine. Interaction experiments were performed between juxtafastigial and Inferior Olive stimulations on 49 PC units in 8-9 day old normal rats. Collisions between impulses set up in CFs were disclosed in 21 out of the 24 PCs which exhibited only one type of CFR. In the three others and in each of the 25 PCs that displayed two types of all-or-none CFRs, or CFRs graded by steps, no collision was detected. Moreover intracellular recordings of epsp's mediated via CFs in PCs of 8-9 day old normal rats revealed that they frequently fluctuated in stepwise fashion. These results demonstrate that in the immature rat more than 50% of PCs are each innervated by at least two distinct CFs; later on, the disappearance of the supernumerary synapses between CF and PC leads, as early as day 15, to the one-to-one relationship between CF and PC.

Modification of retinal ganglion cell morphology by prenatal infusion of tetrodotoxin

Article

Full-text available

Jan 1989

The cellular mechanisms by which the axons of individual neurons achieve their precise terminal branching patterns are poorly understood. In the visual system of adult cats, retinal ganglion cell axons from each eye form narrow cylindrical terminal arborizations restricted to alternate non-overlapping layers within the lateral geniculate nucleus (LGN). During prenatal development, axon arborizations from the two eyes are initially simple in shape and are intermixed with each other; they then gradually segregate to form complex adult-like arborizations in separate eye-specific layers by birth. Here we report that ganglion cell axons exposed to tetrodotoxin (TTX) to block neuronal activity during fetal life fail to form the normal pattern of terminal arborization. Individual TTX-treated axon arborizations are not stunted in their growth, but instead produce abnormally widespread terminal arborizations which extend across the equivalent of approximately two eye-specific layers. These observations suggest that during fetal development of the central nervous system, the formation of morphologically appropriate and correctly located axon terminal arborizations within targets is brought about by an activity-dependent process.

Prenatal and postnatal development of retinogeniculate and retinocollicular projections in the mouse

Article

Full-text available

Jan 1985

The development of retinal projections to the dorsal lateral geniculate nucleus (dLGN) and superior colliculus (SC) has been studied in fetal and neonatal mice of the pigmented C57BL/6 strain, using the anterograde transport of tritiated proline and horseradish peroxidase (HRP). Retinal efferents are present contralaterally just beyond the chiasm at E14. By E16 they have grown into both dLGN and SC. Ipsilateral fibers are limited to the proximal optic tract at E16; their growth into dLGN and SC is delayed until E18-birth. During the first 2 postnatal days, an early population of ipsilateral fibers invades the dLGN. Most of these fibers grow in or around the mediodorsal sector of the dLGN, i.e., the future binocular segment. Fibers are also present, but at lower densities, in the ventral half of the nucleus and thereafter become dispersed or are lost, without at any stage becoming dense. Some denser labeling is also present ipsilaterally in the outer rim of dLGN, just below the optic tract, and later disappears. On the third postnatal day, the ipsilateral fibers establish a deep and denser projection along the medial and dorsal borders of dLGN; this projection overlaps part of the crossed projection, which at this age extends to the whole nucleus. The segregation of each projection starts on the fourth postnatal day, when crossed fibers begin to disappear from the small region of uncrossed projection. This process goes on for another 4 days. During this period, the ipsilateral fibers withdraw from the deepest layer of dLGN, and their terminal density increases gradually; by the eighth postnatal day, both projections are already well separated. Dense crossed projections first appear near the surface of the SC at birth. Prior to this, retinal fibers course throughout neurons of the collicular plate and underneath the pia. The uncrossed fibers invade the SC between birth and P3. They are located preferentially in the anterior and medial aspect of the SC. Subsequently, there occurs a diminution in the laminar and tangential extent of these projections, simultaneously with an intensification of the ipsilateral input to several small, longitudinally oriented clusters located deep to the crossed projections.

Functional synapse elimination in the developing avian cochlear nucleus with simultaneous reduction in cochlear nerve axon branching

Article

Full-text available

Jan 1983

We studied the chick auditory system to determine whether there is a normal developmental reduction in the number of cochlear nerve axons innervating individual cochlear nucleus (nucleus magnocellularis, NM) neurons. We also examined the preterminal branching patterns of cochlear nerve axons during development. The number of cochlear nerve axons innervating individual NM neurons was estimated by counting the increments in the postsynaptic response as the intensity of cochlear nerve electrical stimulation was varied gradually; this number fell from a mean of 4.0 on embryonic day 13 (E13) to a mean of 2.2 on E17 and E18 and the 4th day after hatching. This highly reliable decline in functional convergence was accompanied by a decrease in the number of preterminal branches of cochlear nerve fibers innervating the NM. On E13 and E14, most axons stained by iontophoretic injections of horseradish peroxidase showed two distinct preterminal branches in the NM. By E17 and E18 and thereafter, cochlear nerve axons were unbranched and terminated with a characteristic single large calycine ending in the NM. There are about twice as many cochlear nerve axons as neurons in the NM and the number of fibers in the nerve appears to decline only slightly between E13 and E17. The 50% decline in the number of cochlear nerve axons making functional synapses on individual NM neurons therefore is associated principally with the concurrent elimination of cochlear nerve axon branching in the NM.

Ontogenesis of olivocerebellar relationships. I. Studies by intracellular recordings of the multiple innervation of Purkinje cells by climbing fibers in the developing rat cerebellum

Article

Full-text available

Aug 1981

The establishment of the adult innervation of Purkinje cells (PCs) by climbing fibers (CFs) was studied in the cerebellar vermis of the developing rat. Excitatory postsynaptic potentials (EPSPs) evoked in PCs by activation of the climbing fibers (CF-EPSPs) were recorded intracellularly from a total of 310 cells in young rats aged from 3 to 15 postnatal days. The CF system was activated by electrical stimulation of either the inferior olive (IO) nucleus or the region near the fastigial nucleus (juxtafastigial or JF stimulation). A given PC at each age was considered to be innervated by more than one CF when the amplitude of the spontaneous or evoked CF-EPSPs fluctuated in a stepwise manner. On the other hand, innervation of a PC by a single CF was established on the basis of the all-or-none character of CF-EPSPs. Two parameters were followed throughout development, the percentage of multiply innervated PCs and the mean number of steps in the evoked CF-EPSPs. The data presented confirm the transient multiple innervation of PCs by CFS on postnatal days 8 and 9 (Crépel, F., J. Mariani, and N. Delhaye-Bouchaud (1976) J. Neurobiol. 7: 567-578) and strongly suggest its existence at earlier stages (from postnatal day 3). Moreover, it is shown that the multiple innervation was maximal on postnatal day 5 and then decreased until the innervation by a single CF was established on day 15.

Visual Deprivation Does Not Affect the Orientation and Direction Sensitivity of Relay Cells in the Lateral Geniculate Nucleus of the Cat

Article

Full-text available

Feb 1995

Visual deprivation in early life profoundly affects the characteristic sensitivity of visual cortical cells to stimulus orientation and direction. Recently, relay cells in the lateral geniculate nucleus (LGNd) have been shown to exhibit significant degrees of orientation and direction sensitivity. The effects of visual deprivation upon these properties of subcortical cells are unknown. In this study cats were reared from birth to 6-12 months of age in total darkness; the orientation and direction sensitivities of area 17 (striate cortex) and LGNd cells were compared. All cells were studied using identical quantitative techniques and statistical tests designed to analyze distributions of angles. The results confirm previous work and indicate that the orientation and direction sensitivities of cells in area 17 are profoundly reduced by dark rearing. In marked contrast, these properties of LGNd relay cells are unaffected. The result is that, unlike in the normal cat, in dark-reared cats the orientation and direction sensitivities of cells in the LGNd and visual cortex do not differ. It is concluded that (1) the orientation and direction sensitivities of cortical cells contribute little, if at all, to the sensitivities of LGNd cells since LGNd cells exhibit normal sensitivities even though the cortical cells projecting to them exhibit greatly reduced sensitivities and (2) during normal development intracortical mechanisms appear to expand upon and/or modify the weak orientation and direction sensitivities of their inputs. These intracortical mechanisms depend upon normal visual experience since in dark-reared cats, but not normal ones, the orientation and direction sensitivities of cells in the LGNd and visual cortex do not differ quantitatively or qualitatively.

The Role of Visual Experience in the Development of Columns in Cat Visual Cortex

Article

Full-text available

Feb 1998

The role of experience in the development of the cerebral cortex has long been controversial. Patterned visual experience in the cat begins when the eyes open about a week after birth. Cortical maps for orientation and ocular dominance in the primary visual cortex of cats were found to be present by 2 weeks. Early pattern vision appeared unimportant because these cortical maps developed identically until nearly 3 weeks of age, whether or not the eyes were open. The naïve maps were powerfully dominated by the contralateral eye, and experience was needed for responses to the other eye to become strong, a process unlikely to be strictly Hebbian. With continued visual deprivation, responses to both eyes deteriorated, with a time course parallel to the well-known critical period of cortical plasticity. The basic structure of cortical maps is therefore innate, but experience is essential for specific features of these maps, as well as for maintaining the responsiveness and selectivity of cortical neurons.

Characterization of sensory and corticothalamic excitatory inputs to rat thalamocortical neurones in vitro

Article

Full-text available

Aug 1998

Using an in vitro slice preparation of the rat dorsal lateral geniculate nucleus (dLGN), the properties of retinogeniculate and corticothalamic inputs to thalamocortical (TC) neurones were examined in the absence of GABAergic inhibition. The retinogeniculate EPSP evoked at low frequency (<= 0.1 Hz) consisted of one or two fast‐rising (0.8 ± 0.1 ms), large‐amplitude (10.3 ± 1.6 mV) unitary events, while the corticothalamic EPSP had a graded relationship with stimulus intensity, owing to its slower‐rising (2.9 ± 0.4 ms), smaller‐amplitude (1.3 ± 0.3 mV) estimated unitary components. The retinogeniculate EPSP exhibited a paired‐pulse depression of 60.3 ± 5.6 % at 10 Hz, while the corticothalamic EPSP exhibited a paired‐pulse facilitation of > 150 %. This frequency‐dependent depression of the retinogeniculate EPSP was maximal after the second stimulus, while the frequency‐dependent facilitation of the corticothalamic EPSP was maximal after the fourth or fifth stimulus, at interstimulus frequencies of 1‐10 Hz. There was a short‐term enhancement of the <= 0.1 Hz corticothalamic EPSP (64.6 ± 9.2 %), but not the retinogeniculate EPSP, following trains of stimuli at 50 Hz. The <= 0.1 Hz corticothalamic EPSP was markedly depressed by the non‐NMDA antagonist 1‐(4‐amino‐phenyl)‐4‐methyl‐7,8‐methylene‐dioxy‐5 H‐ 2,3‐benzodiazepine (GYKI 52466), but only modestly by the NMDA antagonist 3‐(( RS )‐2‐carboxypiperazin‐4‐yl)‐propyl‐1‐phosphonic acid ((RS)‐CPP), and completely blocked by the co‐application of GYKI 52466, 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX), (RS)‐CPP and (5 R ,10 S)‐ (+)‐5‐methyl‐10,11‐dihydro‐5 H‐ dibenzo[a,d]cyclohepten‐5,10‐imine (MK‐801). Likewise, the corticothalamic responses to trains of stimuli (1‐500 Hz) were greatly reduced by this combination of ionotropic glutamate receptor antagonists. In the presence of GYKI 52466, CNQX, (RS)‐CPP and MK‐801, residual corticothalamic responses and slow EPSPs, with a time to peak of 2‐10 s, could be generated following trains of five to fifty stimuli. Neither of these responses were occluded by 1 S ,3 R ‐1‐aminocyclopentane‐1,3‐dicarboxylic acid (1S,3R‐ACPD), suggesting they are not mediated via group I and II metabotropic glutamate receptors.

Hensch TK, Fagiolini M, Mataga N, Stryker MP, Baekkeskov S, Kash SF. Local GABA circuit control of experience-dependent plasticity in developing visual cortex. Science 282: 1504-1508

Article

Full-text available

Dec 1998

Sensory experience in early life shapes the mammalian brain. An impairment in the activity-dependent refinement of functional connections within developing visual cortex was identified here in a mouse model. Gene-targeted disruption of one isoform of glutamic acid decarboxylase prevented the competitive loss of responsiveness to an eye briefly deprived of vision, without affecting cooperative mechanisms of synapse modification in vitro. Selective, use-dependent enhancement of fast intracortical inhibitory transmission with benzodiazepines restored plasticity in vivo, rescuing the genetic defect. Specific networks of inhibitory interneurons intrinsic to visual cortex may detect perturbations in sensory input to drive experience-dependent plasticity during development.

Distinct Roles for Ionotropic and Metabotropic Glutamate Receptors in the Maturation of Excitatory Synapses

Article

Full-text available

Apr 2000
J NEUROSCI

We used the single-cell culture preparation to study the role of activity in the development of glutamatergic synapses in vitro. Rat hippocampal cells grown in isolation on glial islands formed functional autaptic connections and continued to elaborate new synapses throughout the 2 week investigation, resulting in increases in both the evoked AMPA receptor (AMPAR) and NMDA receptor (NMDAR) components of the EPSC. Synaptogenesis was not prevented by chronic blockade of sodium channels or all of the known glutamate receptors. Analysis of miniature EPSCs revealed that AMPAR quantal size doubled over time in vitro whereas NMDAR quantal size remained constant. However, the proportion of synaptic responses mediated only by NMDARs increased over time in vitro. The increase in AMPAR quantal size was prevented by TTX and ionotropic glutamate receptor antagonists, whereas the increase in the proportion of NMDAR-only synapses was prevented by metabotropic glutamate receptor antagonists. Notably, chronic NMDAR blockade incubation did not block the formation of the AMPAR EPSC, indicating that NMDAR-dependent plasticity is not necessary for the onset of AMPAR synaptic transmission in this system. We conclude that action potentials and ionotropic glutamate receptor activation are necessary for the developmental increase in AMPAR quantal size and that metabotropic glutamate receptor activation is required for the production of NMDAR-only synapses, but none of these is essential for synapse formation.

Diverse receptive fields in the lateral geniculate nucleus during thalamocortical development

Article

Full-text available

Jul 2000

Most models of thalamocortical development in the visual system assume a homogeneous population of thalamic inputs to the cortex, each with concentric on- or off-center receptive fields. To test this, we made high-resolution spatial maps of receptive fields in the developing ferret lateral geniculate nucleus (LGN). Developing receptive fields (RFs), had a variety of shapes: some concentric, others elongated (like adult cortical receptive fields) and some with 'hot spots' of sensitivity. These receptive fields seemed to arise from convergence of multiple retinal afferents onto LGN neurons. We present a Hebbian model whereby imprecise retinogeniculate connections help refine geniculocortical connections, sharpening both thalamocortical topography and perhaps orientation selectivity.

Malinow R, Malenka RC. AMPA receptor trafficking and synaptic plasticity. Ann Rev Neurosci 25: 103-126

Article

Full-text available

Feb 2002

Activity-dependent changes in synaptic function are believed to underlie the formation of memories. Two prominent examples are long-term potentiation (LTP) and long-term depression (LTD), whose mechanisms have been the subject of considerable scrutiny over the past few decades. Here we review the growing literature that supports a critical role for AMPA receptor trafficking in LTP and LTD, focusing on the roles proposed for specific AMPA receptor subunits and their interacting proteins. While much work remains to understand the molecular basis for synaptic plasticity, recent results on AMPA receptor trafficking provide a clear conceptual framework for future studies.

Takahashi T, Svoboda K, Malinow R. Experience strengthening transmission by driving AMPA receptors into synapses. Science 299: 1585-1588

Article

Full-text available

Apr 2003
SCIENCE

The mechanisms underlying experience-dependent plasticity in the brain may depend on the AMPA subclass of glutamate receptors (AMPA-Rs). We examined the trafficking of AMPA-Rs into synapses in the developing rat barrel cortex. In vivo gene delivery was combined with in vitro recordings to show that experience drives recombinant GluR1, an AMPA-R subunit, into synapses formed between layer 4 and layer 2/3 neurons. Moreover, expression of the GluR1 cytoplasmic tail, a construct that inhibits synaptic delivery of endogenous AMPA-Rs during long-term potentiation, blocked experience-driven synaptic potentiation. In general, synaptic incorporation of AMPA-Rs in vivo conforms to rules identified in vitro and contributes to plasticity driven by natural stimuli in the mammalian brain.

Reversal and Stabilization of Synaptic Modifications in a Developing Visual System

Article

Full-text available

Jul 2003
SCIENCE

Persistent synaptic modifications are essential for experience-dependent refinement of developing circuits. However, in the developing Xenopus retinotectal system, activity-induced synaptic modifications were quickly reversed either by subsequent spontaneous activity in the tectum or by exposure to random visual inputs. This reversal depended on the burst spiking and activation of the N-methyl-D-aspartate subtype of glutamate receptors. Stabilization of synaptic modifications can be achieved by an appropriately spaced pattern of induction stimuli. These findings underscore the vulnerable nature of activity-induced synaptic modifications in vivo and suggest a temporal constraint on the pattern of visual inputs for effective induction of stable synaptic modifications.

Activity-dependent homeostatic specification of transmitter expression in embryonic neurons

Article

Full-text available

Jul 2004
NATURE

Neurotransmitters are essential for interneuronal signalling, and the specification of appropriate transmitters in differentiating neurons has been related to intrinsic neuronal identity and to extrinsic signalling proteins. Here we show that altering the distinct patterns of Ca2+ spike activity spontaneously generated by different classes of embryonic spinal neurons in vivo changes the transmitter that neurons express without affecting the expression of markers of cell identity. Regulation seems to be homeostatic: suppression of activity leads to an increased number of neurons expressing excitatory transmitters and a decreased number of neurons expressing inhibitory transmitters; the reverse occurs when activity is enhanced. The imposition of specific spike frequencies in vitro does not affect labels of cell identity but again specifies the expression of transmitters that are inappropriate for the markers they express, during an early critical period. The results identify a new role of patterned activity in development of the central nervous system.

Selective reconfiguration of layer 4 visual circuitry by visual deprivation

Article

Full-text available

Jan 2005

Visual deprivation during a developmental sensitive period markedly alters visual cortical response properties, but the changes in intracortical circuitry that underlie these effects are poorly understood. Here we use a slice preparation of rat primary visual cortex to show that 2 d of prior visual deprivation early in life increases the excitability of layer 4 circuitry. Slice recordings showed that spontaneous activity of layer 4 star pyramidal neurons increased 25-fold after 2 d of visual deprivation between postnatal days (P) 15 and P17. This effect was mediated by increased net excitatory and decreased net inhibitory synaptic drive. Paired recordings showed that excitatory connections between star pyramidal neurons doubled in amplitude, whereas inhibitory connections decreased or increased depending on the interneuron class. These effects reversed when vision was restored. This dynamic adjustment of the excitation-inhibition balance may allow the networks within layer 4 to maintain stable levels of activity in the face of variable sensory input.

Retinogeniculate Axons Undergo Eye-Specific Segregation in the Absence of Eye-Specific Layers

Article

Jul 2002

The period of susceptibility to the physiological effects of unilateral eye closure in kittens

Article

Mar 1970

1. Kittens were visually deprived by suturing the lids of the right eye for various periods of time at different ages. Recordings were subsequently made from the striate cortex, and responses from the two eyes compared. As previously reported, monocular eye closure during the first few months of life causes a sharp decline in the number of cells that can be influenced by the previously closed eye. 2. Susceptibility to the effects of eye closure begins suddenly near the start of the fourth week, remains high until some time between the sixth and eighth weeks, and then declines, disappearing finally around the end of the third month. Monocular closure for over a year in an adult cat produces no detectable effects. 3. During the period of high susceptibility in the fourth and fifth weeks eye closure for as little as 3‐4 days leads to a sharp decline in the number of cells that can be driven from both eyes, as well as an over‐all decline in the relative influence of the previously closed eye. A 6‐day closure is enough to give a reduction in the number of cells that can be driven by the closed eye to a fraction of the normal. The physiological picture is similar to that following a 3‐month monocular deprivation from birth, in which the proportion of cells the eye can influence drops from 85 to about 7%. 4. Cells of the lateral geniculate receiving input from a deprived eye are noticeably smaller and paler to Nissl stain following 3 or 6 days' deprivation during the fourth week. 5. Following 3 months of monocular deprivation, opening the eye for up to 5 yr produces only a very limited recovery in the cortical physiology, and no obvious recovery of the geniculate atrophy, even though behaviourally there is some return of vision in the deprived eye. Closing the normal eye, though necessary for behavioural recovery, has no detectable effect on the cortical physiology. The amount of possible recovery in the striate cortex is probably no greater if the period of eye closure is limited to weeks, but after a 5‐week closure there is a definite enhancement of the recovery, even though it is far from complete.

Local GABA Circuit Control of Experience-Dependent Plasticity in Developing Visual Cortex

Article

Nov 1998

Synaptic activity and the construction of cortical circuits

Article

Nov 1996

Vision is critical for the functional and structural maturation of connections in the mammalian visual system. Visual experience, however, is a subset of a more general requirement for neural activity in transforming immature circuits into the organized connections that subserve adult brain function. Early in development, internally generated spontaneous activity sculpts circuits on the basis of the brain's "best guess" at the initial configuration of connections necessary for function and survival. With maturation of the sense organs, the developing brain relies less on spontaneous activity and increasingly on sensory experience. The sequential combination of spontaneously generated and experience-dependent neural activity endows the brain with an ongoing ability to accommodate to dynamically changing inputs during development and throughout life.

The Role of Visual Experience in the Development of Columns in Cat Visual Cortex

Article

Jan 1998

Michael C Crair

The role of experience in the development of the cerebral cortex has long been controversial. Patterned visual experience in the cat begins when the eyes open about a week after birth. Cortical maps for orientation and ocular dominance in the primary visual cortex of cats were found to be present by 2 weeks. Early pattern vision appeared unimportant because these cortical maps developed identically until nearly 3 weeks of age, whether or not the eyes were open. The naı̈ve maps were powerfully dominated by the contralateral eye, and experience was needed for responses to the other eye to become strong, a process unlikely to be strictly Hebbian. With continued visual deprivation, responses to both eyes deteriorated, with a time course parallel to the well-known critical period of cortical plasticity. The basic structure of cortical maps is therefore innate, but experience is essential for specific features of these maps, as well as for maintaining the responsiveness and selectivity of cortical neurons.

AMPAR trafficking and synaptic plasticity

Article

Jan 2002

Disruption of reti-nogeniculate afferent segregation by antagonists to NMDA receptors

Article

Jan 1991
NATURE

Ephrin-As and neural activity are required for eye-specific patterning during retinogeniculate mapping

Article

Jul 2005

In mammals, retinal ganglion cell (RGC) projections initially intermingle and then segregate into a stereotyped pattern of eye-specific layers in the dorsal lateral geniculate nucleus (dLGN). Here we found that in mice deficient for ephrin-A2, ephrin-A3 and ephrin-A5, eye-specific inputs segregated but the shape and location of eye-specific layers were profoundly disrupted. In contrast, mice that lacked correlated retinal activity did not segregate eye-specific inputs. Inhibition of correlated neural activity in ephrin mutants led to overlapping retinal projections that were located in inappropriate regions of the dLGN. Thus, ephrin-As and neural activity act together to control patterning of eye-specific retinogeniculate layers.

Principles of Neural Science 4th Ed

Chapter

Jan 2000

Competition in Retinogeniculate Patterning Driven by Spontaneous Activity

Article

Mar 1998

When contacts are first forming in the developing nervous system, many neurons generate spontaneous activity that has been hypothesized to shape appropriately patterned connections. In Mustela putorius furo, monocular intraocular blockade of spontaneous retinal waves of action potentials by cholinergic agents altered the subsequent eye-specific lamination pattern of the lateral geniculate nucleus (LGN). The projection from the active retina was greatly expanded into territory normally belonging to the other eye, and the projection from the inactive retina was substantially reduced. Thus, interocular competition driven by endogenous retinal activity determines the pattern of eye-specific connections from retina to LGN, demonstrating that spontaneous activity can produce highly stereotyped patterns of connections before the onset of visual experience.

Observations on the elimination of polyneural innervation in developing muscle

Article

Oct 1978

1. The mechanism responsible for the elimination of polyneuronal innervation in developing rat soleus muscles was studied electrophysiologically and histologically. 2. Initially all the axons contacting a single end-plate have simple bulbous terminals. As elimination proceeds one axon develops terminal branches while the other terminals remain bulbous and may be seen in contact with, or a short distance away from, the end-plate. It is suggested that the branched terminal remains in contact with the muscle fibre while the other terminals withdraw. 3. At a time when polyneuronal innervation can no longer be detected electrophysiologically, the histological technique still shows the presence of end-plates contacted by more than one nerve terminal. 4. The effect of activity on the disappearance of polyneuronal innervation was examined. Activity was increased by electrical stimulation of the right sciatic nerve. This procedure also produced reflex activity in the contralateral limb. In both cases polyneuronal innervation was eliminated more rapidly in the active muscles. 5. The finding that proteolytic enzymes are released from muscles treated with acetylcholine (ACh), and the observation of the more rapid elimination of supernumerary terminals at the end-plates of active muscles, lead to the suggestion that superfluous nerve-muscle contacts are removed by the proteolytic enzymes in response to neuromuscular activity. The selective stabilization of only one of the terminals is discussed in the light of these results.

Development of single-unit responses in kitten's lateral geniculate nucleus

Article

Dec 1978

1. In the lateral geniculate nucleus (LGN) of 18 kittens whose ages ranged from 6 to 40 days, 445 cells were studied. 2. LGN cells of kittens younger than 21 days are characterized by very low maintained rates, long latencies to full-field flash, response fatigue, large receptive field, absence of surround responses and surround inhibition, poor responses to fast-moving stimuli, and low-amplitude responses to flashing spots. 3. Cells were characterized as sustained or transient, and on, off, or on-off by their responses to flashing spots of light, and as X-like of Y-like by their responses to contrast reversal. Prior to 21 days, cells are hard to classify as X or Y. 4. A large proportion of cells in kitten LGN have both on- and off-responses to small and center-sized spots of light. This proportion decreases with development. 5. A small number of cells develop mature receptive-field properties very early (14--20 days). These are cells with X-type responses (linear summation) to contrast reversal and tend to have sustained responses to flashing spots. 6. Y-like cells, with nonlinear summation, develop mature receptive-field properties later than 34 days of age and later than all X-cells. 7. We conclude that there are different developmental patterns for cells of the kitten LGN. These different patterns may be important in determining the visual responses of cortical cells and their degree of susceptibility to environmental modification.

Recovery of function in cat visual cortex following prolonged deprivation

Article

Jun 1976

Evidence that there is a critical period during which response characteristics of neurons in visual cortex of the cat may be influenced has been provided in several studies, which suggest that the period of influence is restricted to the first few months of life. Using a somewhat different experimental procedure, we have obtained evidence that cortical units retain plasticity long after the end of this period has passed. In our procedure prolonged visual deprivation was followed by exposure in a normal visual environment. The animals were maintained throughout the first year of life either in total darkness or in an enclosure illuminated intermittently by a strobe light. Following the period of deprivation, electrophysiologic recordings were taken from some of these animals. The remaining cats were permitted 6–12 months in a normally-illuminated environment prior to recording. Cats of the same age reared from birth in a normally lit environment were also recorded. Cortical neurons in cats deprived of any normal visual experience rarely show orientation selective responses. In animals allowed subsequent normal visual experience about one-half of the units studied exhibited this property. This level of response specificity is intermediate between that of normally-reared and recently-deprived animals. While most cortical units in normally-reared cats exhibit direction selectivity, this property is rarely observed in the “recovery” cats. A number of unit types which are rarely observed in either normal or totally deprived animals were encountered in cats that had normal exposure following prolonged deprivation. A convergent strabismus was observed, in contrast with the divergent strabismus often shown by cats immediately following prolonged visual deprivation. This shows that ocular alignment as well as cortical unit properties can remain plastic in the adult.

Carmignoto, G. & Vicini, S. Activity-dependent decrease in NMDA receptor responses during development of the visual cortex. Science 258, 1007-1011

Article

Dec 1992

Plasticity of the developing visual system has been regarded as the best model for changes of neuronal connections under the influence of the environment. N-methyl-D-aspartate (NMDA) receptors are crucial for experience-dependent synaptic modifications that occur in the developing visual cortex. NMDA-mediated excitatory postsynaptic currents (EPSCs) in layer IV neurons of the visual cortex lasted longer in young rats than in adult rats, and the duration of the EPSCs became progressively shorter, in parallel with the developmental reduction in synaptic plasticity. This decrease in NMDA receptor-mediated EPSC duration is delayed when the animals are reared in the dark, a condition that prolongs developmental plasticity, and is prevented by treatment with tetrodotoxin, a procedure that inhibits neural activity. Application of L-glutamate to outside-out patches excised from layer IV neurons of young, but not of adult, rats activated prolonged bursts of NMDA channel openings. A modification of the NMDA receptor gating properties may therefore account for the age-dependent decline of visual cortical plasticity.

Developmental regulation of NMDA receptor-mediated synaptic currents at a central synapse

Article

Jul 1992

Shaul Hestrin

The central nervous system has extraordinary plasticity in early life. This is thought to involve N-methyl-D-aspartate (NMDA) receptors which, along with the non-NMDA receptors, mediate fast excitatory synaptic transmission. Although NMDA receptors may be transiently enhanced early in life, it has not been possible to demonstrate directly a functional change in the NMDA receptor-mediated synaptic response because of the voltage-dependence of the NMDA conductance and the overlapping inhibitory synaptic conductances. Here I report that the duration of evoked NMDA-receptor-mediated excitatory postsynaptic currents (e.p.s.cs) in the superior colliculus is several times longer at early developmental stages compared to that measured in older animals. In contrast, the amplitude of NMDA-receptor-mediated miniature e.p.s.cs does not change during development. The kinetic response of excised membrane patches to a brief activation of NMDA receptors is similar to that of the NMDA e.p.s.c, which suggests that the time course of the NMDA e.p.s.c. in the superior colliculus reflects slow NMDA channel properties as in the hippocampus. Therefore, these data indicate that the molecular properties of NMDA receptors are developmentally regulated and thus may be controlling the ability of synapses to change in early life.

Disruption of retinogeniculate afferent segregation by antagonists to NMDA receptors

Article

Jul 1991

Afferent activity has an important role in the formation of connections in the developing mammalian visual system. But the extent to which the activity of target neurons shapes patterns of afferent termination and synaptic contact is not known. In the ferret's visual pathway, retinal ganglion cell axons from each eye segregate early in development into eye-specific laminae in the lateral geniculate nucleus (LGN). The dorsal laminae (termed laminae A and A1) then segregate further into inner and outer sublaminae that retain input from on-centre and off-centre retinal axons, respectively. Thus, individual retinogeniculate axons form terminal arbors within laminae A and A1 that are restricted to one inner or outer sublamina. We report here that blockade of N-methyl-D-aspartate (NMDA) receptors on LGN cells with specific antagonists during the period of sublamina formation prevents retinal afferents from segregating into 'On' and 'Off' sublaminae. Retinogeniculate axons have arbors that are not restricted appropriately, or are restricted in size but inappropriately positioned within the eye-specific laminae. NMDA receptor antagonists may specifically disrupt a mechanism by which LGN neurons detect correlated afferent and target activity, and have been shown to reduce retinogeniculate transmission more generally, causing LGN cells to have markedly reduced levels of activity. These results therefore indicate that the activity of postsynaptic cells can significantly influence the patterning of inputs and the structure of presynaptic afferents during development.

Synchronous Bursts of Action Potentials in Ganglion Cells of the Developing Mammalian Retina

Article

Jun 1991

The development of orderly connections in the mammalian visual system depends on action potentials in the optic nerve fibers, even before the retina receives visual input. In particular, it has been suggested that correlated firing of retinal ganglion cells in the same eye directs the segregation of their synaptic terminals into eye-specific layers within the lateral geniculate nucleus. Such correlations in electrical activity were found by simultaneous recording of the extracellular action potentials of up to 100 ganglion cells in the isolated retina of the newborn ferret and the fetal cat. These neurons fired spikes in nearly synchronous bursts lasting a few seconds and separated by 1 to 2 minutes of silence. Individual bursts consisted of a wave of excitation, several hundred micrometers wide, sweeping across the retina at about 100 micrometers per second. These concerted firing patterns have the appropriate spatial and temporal properties to guide the refinement of connections between the retina and the lateral geniculate nucleus.

Galli, L. & Maffei, L. Spontaneous impulse activity of rat retinal ganglion cells in prenatal life. Science 242, 90-91

Article

Nov 1988

The existence of spontaneous neural activity in mammalian retinal ganglion cells during prenatal life has long been suspected. This activity could play a key role in the refinement of retinal projections during development. Recordings in vivo from the retinas of rat fetuses between embryonic day 17 and 21 found action potentials in spontaneously active ganglion cells at all the ages studied.

Prenatal Tetrodotoxin Infusion Blocks Segregation of Retinogeniculate Afferents

Article

Nov 1988

In the adult mammalian visual system, ganglion cell axons from the two eyes are segregated from each other into separate layers within their principal target, the lateral geniculate nucleus. The involvement of spontaneously generated action potential activity in the process of segregation was investigated during the fetal period in which segregation normally occurs in the cat, between embryonic day 45 (E45) and birth (E65). Tetrodotoxin, which blocks the voltage-sensitive sodium channel, was used to prevent action potentials. Fetuses received continuous intracranial infusions of tetrodotoxin from osmotic minipumps implanted in utero on E42. After a 2-week infusion, intraocular injections of anterograde tracers revealed that tetrodotoxin prevented segregation. The contralateral projection filled the lateral geniculate nucleus uniformly, and the ipsilateral projection expanded to occupy most of what would normally be contralaterally innervated layer A. Thus, in the fetus, long before the onset of vision, spontaneous action potential activity is likely to be present in the visual system and to contribute to the segregation of the retinogeniculate pathway.

Organisation and post-natal development of the monkey's lateral geniculate

Article

Dec 1986

We have studied the properties of neurones in the lateral geniculate nucleus (l.g.n.) of Old World monkeys, both in mature animals and throughout post-natal development. Cells were classified as X (linear) or Y (non-linear) on the basis of their responses to contrast-reversing achromatic gratings ('null position test'). In older animals virtually all parvocellular neurones and the majority of magnocellular units were X cells; only about 15% of magnocellular neurones displayed highly non-linear spatial summation, with no 'null position', typical of Y cells. X cells could not reliably be distinguished from Y cells, nor magnocellular from parvocellular, on the basis of their temporal patterns of discharge. Some Y cells responded transiently to contrast reversal of a grating far from the receptive field but X cells showed little or no such 'shift effect'. The spatial resolution of mature l.g.n. cells varied with the eccentricity of their receptive fields such that the best of them, at each point in the visual field, resolved drifting achromatic gratings about as well as a human observer. X cells in parvocellular and magnocellular layers had similar 'acuities', even in the central foveal representation, but Y cells generally had poorer resolution. Receptive fields in the temporal retina tended to have lower resolution than those at comparable eccentricities in the nasal retina. Even on the day of birth all cells we studied responded to visual stimulation and virtually all could be classified as X or Y. The laminar distribution of cell types and the general morphological appearance of the nucleus seemed very similar to those in the adult, but neurones in very young animals had low spontaneous activity, sluggish responses, and latencies to visual stimulation longer than any we saw in the adult. Until 3 weeks of age or so, many neurones suffered cumulative 'fatigue' when visually stimulated over several minutes. Visual latency was essentially mature by about 10 weeks. In the l.g.n. of the neonatal monkey there was little variation in neuronal 'acuity' with eccentricity: even in the foveal area the best cells could resolve only about 5 cycles/deg. Over the first year or more of life there is a gradual increase in responsiveness and about a 7-fold improvement in spatial resolution for foveal l.g.n. cells, correlating roughly with the behavioural maturation of visual acuity.

Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron 12: 529-540

Article

Apr 1994
NEURON

An in situ study of mRNAs encoding NMDA receptor subunits in the developing rat CNS revealed that, at all stages, the NR1 gene is expressed in virtually all neurons, whereas the four NR2 transcripts display distinct expression patterns. NR2B and NR2D mRNAs occur prenatally, whereas NR2A and NR2C mRNAs are first detected near birth. All transcripts except NR2D peak around P20. NR2D mRNA, present mainly in midbrain structures, peaks around P7 and thereafter decreases to adult levels. Postnatally, NR2B and NR2C transcript levels change in opposite directions in the cerebellar internal granule cell layer. In the adult hippocampus, NR2A and NR2B mRNAs are prominent in CA1 and CA3 pyramidal cells, but NR2C and NR2D mRNAs occur in different subsets of interneurons. Recombinant binary NR1-NR2 channels show comparable Ca2+ permeabilities, but marked differences in voltage-dependent Mg2+ block and in offset decay time constants. Thus, the distinct expression profiles and functional properties of NR2 subunits provide a basis for NMDA channel heterogeneity in the brain.

Katz LC, Shatz CJ. Synaptic activity and the construction of cortical circuits. Science 274: 1133-1138

Article

Dec 1996

Novel method of chronically blocking retinal activity

Article

Mar 1999
J NEUROSCI METH

The ethylene-vinyl acetate copolymer Elvax has been used as a vehicle to deliver bioactive substances to discrete areas of the nervous system. Here we report a novel use of Elvax to chronically block retinal activity. Small pieces of Elvax containing the sodium channel blocker tetrodotoxin (TTX) were surgically implanted into the vitreous humor of ferret eyes. Observations of the light-induced pupillary reflex combined with electrophysiological assays of vitreous humor confirmed that these implants completely blocked retinal activity for up to 25 days without apparent retinal damage. The advantages of this procedure over previous methods requiring multiple daily injections of TTX, and alternative experimental applications are discussed.

The role of spontaneous retinal activity before eye opening in the maturation of form and function in the retinogeniculate pathway of the ferret

Article

May 1999

During early mammalian development, inputs from the two retinas intermix within the lateral geniculate nucleus (LGN), then segregate during the first postnatal week into layers that receive input from a single retina. Functionally, the LGN also changes markedly during the first postnatal month; early geniculate responses to retinal input are mainly excitatory, then inhibitory circuits mature within the LGN. These remarkable changes in form and function of the retinogeniculate pathway occur at a time when patterned visual activity is not present, but retinal ganglion cells already manifest spontaneous action potential activity. To examine the role of early retinal activity in these critical developmental processes, we placed the slow release polymer Elvax embedded with tetrodotoxin (TTX) into the vitreous chamber of one or both eyes of neonatal ferrets. Animals receiving monocular injection of TTX had the other eye treated with Elvax containing control citrate buffer. Intraocular injection of horseradish peroxidase was made at the end of the period of TTX treatment to reveal the retinal terminals in the LGN. Chronic monocular or binocular blockade of retinal activity during the first postnatal week did not prevent eye-specific segregation, although it made the boundaries between layers less distinct. Retinal terminals ended preferentially in the appropriate layer, but a large number of terminals were also present in the inappropriate layer. Further segregation was achieved during the second postnatal week of activity blockade, when most retinal terminals ended preferentially in the appropriate geniculate layer and sharper layer boundaries were present. However, a small but significant number of terminals still extended into the inappropriate layer. Together, these findings indicate that monocular as well as binocular blockade of retinal activity resulted in some anomalous retinogeniculate projections and delayed eye-specific patterning, but segregation was largely intact at the end of the second postnatal week. We also report here that intraocular tetrodotoxin had a marked effect on the maturation of intrinsic geniculate circuits prior to eye opening. Whole-cell patch-clamp recordings in the LGN slice preparation revealed that activity blockade prevented the maturation of the slow, but not the fast, hyperpolarizing potential of LGN neurons during the first postnatal month and up to P38, the oldest age studied. In conclusion, these results indicate that spontaneous retinal activity modulates the time course of binocular segregation but does not alone account for the segregation of retinogeniculate terminals. However, early retinal activity plays an important role in developing the intrinsic circuitry of the LGN.

Role of AMPA Receptor Cycling in Synaptic Transmission and Plasticity

Article

Dec 1999
NEURON

Compounds known to disrupt exocytosis or endocytosis were introduced into CA1 pyramidal cells while monitoring excitatory postsynaptic currents (EPSCs). Disrupting exocytosis or the interaction of GluR2 with NSF caused a gradual reduction in the AMPAR EPSC, while inhibition of endocytosis caused a gradual increase in the AMPAR EPSC. These manipulations had no effect on the NMDAR EPSC but prevented the subsequent induction of LTD. These results suggest that AMPARs, but not NMDARs, cycle into and out of the synaptic membrane at a rapid rate and that certain forms of synaptic plasticity may utilize this dynamic process.

Developmental Remodeling of the Retinogeniculate Synapse

Article

Dec 2000
NEURON

Anatomical rearrangement of retinogeniculate connections contributes to the refinement of synaptic circuits in the developing visual system, but the underlying changes in synaptic function are unclear. Here, we study such changes in mouse brain slices. Each geniculate cell receives a surprisingly large number of retinal inputs (>20) well after eye-specific zones are formed. All but one to three of these inputs are eliminated over a 3-week period spanning eye opening. Remaining inputs are strengthened approximately 50-fold, in part through an increase in quantal size, but primarily through an increase in the number of release sites. Changes in release probability do not contribute significantly. Thus, a redistribution of release sites from many inputs to few inputs at this late developmental stage contributes to the precise receptive fields of thalamic relay neurons.

Retinogeniculate Axons Undergo Eye-Specific Segregation in the Absence of Eye-Specific Layers

Article

Aug 2002
J NEUROSCI

Spontaneous retinal activity mediated by cholinergic transmission regulates the segregation of retinal ganglion cell axons in the lateral geniculate nucleus of the thalamus into eye-specific layers. The details of how the layers form are unknown. Mice lacking the beta2 subunit of the neuronal nicotinic acetylcholine receptor lack ACh-mediated waves and as a result, do not form eye-specific layers at any stage of development. However, during the second postnatal week, beta2-/- mice have glutamate-mediated waves. Here we show that after the first postnatal week, even in the absence of layers, retinothalamic axons segregate into an unlayered, patchy distribution of eye-specific regions. These results indicate that spontaneous neural activity may independently regulate eye-specific segregation and the formation of layers at the developing retinothalamic projection.

Functional Differentiation of Multiple Climbing Fiber Inputs during Synapse Elimination in the Developing Cerebellum

Article

Jul 2003
NEURON

We studied how physiological properties of cerebellar climbing fiber (CF) to Purkinje cell (PC) synapses change during developmental transition from multiple to mono CF innervation onto each PC. From P3 to P6, differences in the strengths of multiple CFs became larger. Around P10, each PC was either monoinnervated by one strong CF (CF-mono) or multiply innervated by one strong CF (CF-multi-S) plus a few weaker CFs (CF-multi-W). We show that simultaneous release of multiple vesicles per site occurs normally from CF-multi-S, CF-mono, and mature CFs, but less frequently from CF-multi-W and neonatal CFs. We also present evidence suggesting that weaker CFs with lower probability of multivesicular release would be withdrawn preferentially. The results suggest that differentiation into strong and weak CFs with high and low probabilities of multivesicular release precedes developmental CF synapse elimination.

Visual Stimulation Is Required for Refinement of ON and OFF Pathways in Postnatal Retina

Article

Aug 2003
NEURON

ON and OFF pathways separately relay increment and decrement luminance signals from retinal bipolar cells to cortex. ON-OFF retinal ganglion cells (RGCs) are activated via synaptic inputs onto bistratified dendrites localized in the ON and OFF regions of the inner plexiform layer. Postnatal maturational processes convert bistratifying ON-OFF RGCs to monostratifying ON and OFF RGCs. Although visual deprivation influences refinement of higher visual centers, no previous studies suggest that light regulates either the development of the visual-evoked signaling in retinal ON and OFF pathways, nor pruning of bistratified RGC dendrites. We find that dark rearing blocks both the maturational loss of ON-OFF responsive RGCs and the pruning of dendrites. Thus, in retina, there is a previously unrecognized, pathway-specific maturation that is profoundly affected by visual deprivation.

The role of neuronal identity in synaptic competition

Article

Aug 2003
NATURE

In developing mammalian muscle, axon branches of several motor neurons co-innervate the same muscle fibre. Competition among them results in the strengthening of one and the withdrawal of the rest. It is not known why one particular axon branch survives or why some competitions resolve sooner than others. Here we show that the fate of axonal branches is strictly related to the identity of the axons with which they compete. When two neurons co-innervate multiple target cells, the losing axon branches in each contest belong to the same neuron and are at nearly the same stage of withdrawal. The axonal arbor of one neuron engages in multiple sets of competitions simultaneously. Each set proceeds at a different rate and heads towards a common outcome based on the identity of the competitor. Competitive vigour at each of these sets of local competitions depends on a globally distributed resource: neurons with larger arborizations are at a competitive disadvantage when confronting neurons with smaller arborizations. An accompanying paper tests the idea that the amount of neurotransmitter released is this global resource.

Visually Driven Regulation of Intrinsic Neuronal Excitability Improves Stimulus Detection In Vivo

Article

Sep 2003
NEURON

Neurons adapt their electrophysiological properties to maintain stable levels of electrical excitability when faced with a constantly changing environment. We find that exposing freely swimming Xenopus tadpoles to 4-5 hr of persistent visual stimulation increases the intrinsic excitability of optic tectal neurons. This increase is correlated with enhanced voltage-gated Na+ currents. The same visual stimulation protocol also induces a polyamine synthesis-dependent reduction in Ca2+-permeable AMPAR-mediated synaptic drive, suggesting that the increased excitability may compensate for this reduction. Accordingly, the change in excitability was prevented by blocking polyamine synthesis during visual stimulation and was rescued when Ca2+-permeable AMPAR-mediated transmission was selectively reduced. The changes in excitability also rendered tectal cells more responsive to synaptic burst stimuli, improving visual stimulus detection. The synaptic and intrinsic adaptations function together to keep tectal neurons within a constant operating range, while making the intact visual system less responsive to background activity yet more sensitive to burst stimuli.

Single-Cell Responses in Striate Cortex of Kittens Deprived of Vision in One Eye

Article

Dec 1963

Eye Opening Rapidly Induces Synaptic Potentiation and Refinement

Article

Aug 2004
NEURON

NMDA receptor (NMDAR)-mediated increases in AMPA receptor (AMPAR) currents are associated with long-term synaptic potentiation (LTP). Here, we provide evidence that similar changes occur in response to normal increases in sensory stimulation during development. Experiments discriminated between eye opening-induced and age-dependent changes in synaptic currents. At 6 hr after eye opening (AEO), a transient population of currents mediated by NR2B-rich NMDARs increase significantly, and silent synapses peak. Sustained increases in evoked and miniature AMPAR currents occur at 12 hr AEO. Significant changes in AMPAR:NMDAR evoked current ratios, contacts per axon, and inputs per cell are present at 24 hr AEO. The AMPAR current changes are those seen in vitro during NMDAR-dependent LTP. Here, they are a consequence of eye opening and are associated with a new wave of synaptic refinement. These data also suggest that new NR2B-rich NMDAR currents precede and may initiate this developmental synaptic potentiation and functional tuning.

Normal Patterns of Spontaneous Activity Are Required for Correct Motor Axon Guidance and the Expression of Specific Guidance Molecules

Article

Oct 2004
NEURON

Rhythmic spontaneous electrical activity occurs in many parts of the developing nervous system, where it plays essential roles in the refinement of neural connections. By blocking or slowing this bursting activity, via in ovo drug applications at precise developmental periods, we show that such activity is also required at much earlier stages for spinal motoneurons to accurately execute their first major dorsal-ventral pathfinding decision. Blockade or slowing of rhythmic bursting activity also prevents the normal expression patterns of EphA4 and polysialic acid on NCAM, which may contribute to the pathfinding errors observed. More prolonged (E2-5) blockade resulted in a downregulation of LIM homeodomain transcription factors, but since this occurred only after the pathfinding errors and alterations in guidance molecules, it cannot have contributed to them.

Distinct Roles for Spontaneous and Visual Activity in Remodeling of the Retinogeniculate Synapse

Abstract

No full-text available

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