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ABSTRACT: The morphological and functional development of the vertebrate nervous system is initially governed by genetic factors and subsequently refined by neuronal activity. However, fundamental features of the nervous system emerge before sensory experience is possible. Thus, activity-dependent development occurring before the onset of experience must be driven by spontaneous activity, but the origin and nature of activity in vivo remains largely untested. Here we use optical methods to show in live neonatal mice that waves of spontaneous retinal activity are present and propagate throughout the entire visual system before eye opening. This patterned activity encompassed the visual field, relied on cholinergic neurotransmission, preferentially initiated in the binocular retina and exhibited spatiotemporal correlations between the two hemispheres. Retinal waves were the primary source of activity in the midbrain and primary visual cortex, but only modulated ongoing activity in secondary visual areas. Thus, spontaneous retinal activity is transmitted through the entire visual system and carries patterned information capable of guiding the activity-dependent development of complex intra- and inter-hemispheric circuits before the onset of vision.
Nature 10/2012; 490(7419):219-25. · 36.28 Impact Factor
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ABSTRACT: Binocular competition is thought to drive eye-specific segregation in the developing visual system, potentially through Hebbian synaptic learning rules that are sensitive to correlations in afferent activity. Altering retinal activity can disrupt eye-specific segregation, but little is known about the temporal features of binocular activity that modulate visual map development. We used optogenetic techniques to directly manipulate retinal activity in vivo and identified a critical period before eye opening in mice when specific binocular features of retinal activity drive visual map development. Synchronous activation of both eyes disrupted segregation, whereas asynchronous stimulation enhanced segregation. The optogenetic stimulus applied was spatially homogenous; accordingly, retinotopy of ipsilateral projections was markedly perturbed, but contralateral retinotopy was unaffected or even improved. These results provide direct evidence that the synchrony and precise temporal pattern of binocular retinal activity during a critical period in development regulates eye-specific segregation and retinotopy in the developing visual system.
Nature Neuroscience 11/2011; 15(2):298-307. · 15.53 Impact Factor
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ABSTRACT: Neural activity during vertebrate development has been unambiguously shown to play a critical role in sculpting circuit formation and function. Patterned neural activity in various parts of the developing nervous system is thought to modulate neurite outgrowth, axon targeting, and synapse refinement. The nature and role of patterned neural activity during development has been classically studied with in vitro preparations using pharmacological manipulations. In this review we discuss newly available and developing molecular-genetic tools for the visualization and manipulation of neural activity patterns specifically during development.
Frontiers in Molecular Neuroscience 01/2011; 4:43.
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ABSTRACT: In human patients, cortical dysplasia produced by Doublecortin (DCX) mutations lead to mental retardation and intractable infantile epilepsies, but the underlying mechanisms are not known. DCX(-/-) mice have been generated to investigate this issue. However, they display no neocortical abnormality, lessening their impact on the field. In contrast, in utero knockdown of DCX RNA produces a morphologically relevant cortical band heterotopia in rodents. On this preparation we have now compared the neuronal and network properties of ectopic, overlying, and control neurons in an effort to identify how ectopic neurons generate adverse patterns that will impact cortical activity. We combined dynamic calcium imaging and anatomical and electrophysiological techniques and report now that DCX(-/-)EGFP(+)-labeled ectopic neurons that fail to migrate develop extensive axonal subcortical projections and retain immature properties, and most of them display a delayed maturation of GABA-mediated signaling. Cortical neurons overlying the heterotopia, in contrast, exhibit a massive increase of ongoing glutamatergic synaptic currents reflecting a strong reactive plasticity. Neurons in both experimental fields are more frequently coactive in coherent synchronized oscillations than control cortical neurons. In addition, both fields displayed network-driven oscillations during evoked epileptiform burst. These results show that migration disorders produce major alterations not only in neurons that fail to migrate but also in their programmed target areas. We suggest that this duality play a major role in cortical dysfunction of DCX brains.
Journal of Neuroscience 02/2009; 29(2):313-27. · 7.11 Impact Factor
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ABSTRACT: Developing cortical networks generate a variety of coherent activity patterns that participate in circuit refinement. Early network oscillations (ENOs) are the dominant network pattern in the rodent neocortex for a short period after birth. These large-scale calcium waves were shown to be largely driven by glutamatergic synapses albeit GABA is a major excitatory neurotransmitter in the cortex at such early stages, mediating synapse-driven giant depolarizing potentials (GDPs) in the hippocampus. Using functional multineuron calcium imaging together with single-cell and field potential recordings to clarify distinct network dynamics in rat cortical slices, we now report that the developing somatosensory cortex generates first ENOs then GDPs, both patterns coexisting for a restricted time period. These patterns markedly differ by their developmental profile, dynamics, and mechanisms: ENOs are generated before cortical GDPs (cGDPs) by the activation of glutamatergic synapses mostly through NMDARs; cENOs are low-frequency oscillations (approximately 0.01 Hz) displaying slow kinetics and gradually involving the entire network. At the end of the first postnatal week, GABA-driven cortical GDPs can be reliably monitored; cGDPs are recurrent oscillations (approximately 0.1 Hz) that repetitively synchronize localized neuronal assemblies. Contrary to cGDPs, cENOs were unexpectedly facilitated by short anoxic conditions suggesting a contribution of glutamate accumulation to their generation. In keeping with this, alterations of extracellular glutamate levels significantly affected cENOs, which are blocked by an enzymatic glutamate scavenger. Moreover, we show that a tonic glutamate current contributes to the neuronal membrane excitability when cENOs dominate network patterns. Therefore, cENOs and cGDPs are two separate aspects of neocortical network maturation that may be differentially engaged in physiological and pathological processes.
Journal of Neuroscience 12/2008; 28(48):12851-63. · 7.11 Impact Factor
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ABSTRACT: During forebrain development the lateral cortical stream (LCS) supplies neurons to structures in the ventral telencephalon including the amygdala and piriform cortex. In the current study, we used spatially directed in utero electroporation and RNAi to investigate mechanisms of migration to the ventral telencephalon. Cells labeled by in utero electroporation of the lateral ventricular zone migrated into the LCS, and entered the lateral neocortex, piriform cortex and amygdala, where they differentiated primarily as pyramidal neurons. RNAi of DCX or LIS1 disrupted migration into amygdala and piriform cortex and caused many neurons to accumulate in the external and amygdalar capsules. RNAi of LIS1 and DCX had similar as well as distinguishable effects on the pattern of altered migration. Combinatorial RNAi of LIS1 and DCX further suggested interaction in the functions of LIS1 and DCX on the morphology and migration of migrating neurons in the LCS. Together, these results confirm that the LCS contributes pyramidal neurons to ventral forebrain structures and reveals that DCX and LIS1 have important functions in this major migratory pathway in the developing forebrain.
Developmental Neuroscience 02/2008; 30(1-3):144-56. · 3.63 Impact Factor
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ABSTRACT: The dentate gyrus is a site of continual neurogenesis in the postnatal mammalian brain. Here we investigated postnatal neurogenesis in the citron kinase (citron-K) null-mutant rat (flathead). The flathead rat has substantial deficits in embryonic neurogenesis that are due to failed cytokinesis and cell death. We report here the loss of citron-K function has an even severer effect on postnatal neurogenesis in the dentate gyrus. Analysis of phosphorylated histone H3 expression in postnatal neurogenic regions of the flathead mutant revealed a complete lack of mitotic cells in the dentate gyrus and a large reduction in the number of dividing cells in the flathead subventricular zone. Examination of 5-bromodeoxyuridine incorporation in the flathead rat revealed that the flathead rat had a 99% reduction in the number of newly generated cells in the dentate gyrus at postnatal day 10. In addition, doublecortin-positive cells were essentially absent from the postnatal flathead dentate gyrus which also lacked the vimentin- and nestin-positive radial glia scaffold that defines the neurogenic niche in the postnatal subgranular zone. Together these results indicate that postnatal neurogenesis in the dentate gyrus is eliminated by loss of citron-K function, and suggests that a citron-K-dependent progenitor lineage forms the postnatal neuronal progenitor population in the dentate gyrus.
Developmental Neuroscience 02/2007; 29(1-2):113-23. · 3.63 Impact Factor
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ABSTRACT: The neurogenic potential of the postnatal neocortex has not been tested previously with a combination of both retroviral and bromodeoxyuridine (BrdU) labeling. Here we report that injections of enhanced green fluorescent protein (eGFP) retrovirus into 134 postnatal rats resulted in GFP labeling of 642 pyramidal neurons in neocortex. GFP-labeled neocortical pyramidal neurons, however, unlike GFP-labeled glia, did not incorporate BrdU. Closer inspection of retrovirally labeled neurons revealed microglia fused to the apical dendrites of labeled pyramidal neurons. Retroviral infection of mixed cultures of cortical neurons and glia confirmed the presence of specific neuronal-microglial fusions. Microglia did not fuse to other glial cell types, and cultures not treated with retrovirus lacked microglial-neuronal fusion. Furthermore, activation of microglia by lipopolysaccharide greatly increased the virally induced fusion of microglia to neurons in culture. These results indicate a novel form of specific cell fusion between neuronal dendrites and microglia and further illustrate the need for caution when interpreting evidence for neuronogenesis in the postnatal brain.
Journal of Neuroscience 12/2006; 26(44):11413-22. · 7.11 Impact Factor
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Experimental Neurology 06/2006; 199(1):5-9. · 4.70 Impact Factor
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ABSTRACT: Mutations in the doublecortin gene (DCX) in humans cause malformation of the cerebral neocortex. Paradoxically, genetic deletion of Dcx in mice does not cause neocortical malformation. We used electroporation of plasmids encoding short hairpin RNA to create interference (RNAi) of DCX protein in utero, and we show that DCX is required for radial migration in developing rat neocortex. RNAi of DCX causes both cell-autonomous and non-cell autonomous disruptions in radial migration, and creates two disruptions in neocortical development. First, many neurons prematurely stop migrating to form subcortical band heterotopias within the intermediate zone and then white matter. Second, many neurons migrate into inappropriate neocortical lamina within normotopic cortex. In utero RNAi can therefore be effectively used to study the specific cellular roles of DCX in neocortical development and to produce an animal model of double cortex syndrome.
Nature Neuroscience 01/2004; 6(12):1277-83. · 15.53 Impact Factor
