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The modulation of cortical activity by GABAergic interneurons is required for normal brain function and is achieved through the immense level of heterogeneity within this neuronal population. Cortical interneurons share a common origin in the ventral telencephalon, yet during the maturation process diverse subtypes are generated that form the chara...
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... first event would state that interneurons are spec- ified at the time of birth and therefore subtype specifi- cation is largely defined within the GE. The obvious molecular candidates would be transcription factors ( table 1 ), and Rubenstein and colleagues have been influential in discovering an array of factors that define the GE as a distinct developmental domain [39,[64][65][66][67][68][69] . Dlx1 and Dlx2 are expressed throughout the SVZ of the GE and confer an interneuron fate upon the newly born cells. ...
Context 2
... terestingly, although a small number of interneurons have been observed moving in and out of the CP at early stages of corticogenesis [31,[175][176][177] , they do not become established in their correct layer until late embryonic/ear- ly postnatal stages, well after their contemporaneously born pyramidal neuron counterparts [180,200] . It has been suggested that cues from the cortex, rather than in- trinsic genetic programming, controls interneuron lami- nation [195,201] ( table 1 ). One well-known molecule thought to play a major role in cortical lamination is the secreted extracellular matrix protein reelin. ...
Similar publications
Appropriate interneuron migration and distribution is essential for the construction of functional neuronal circuitry and the maintenance of excitatory/inhibitory balance in the brain. Gamma-aminobutyric acid (GABA)ergic interneurons originating from the ventral telencephalon choreograph a complex pattern of migration to reach their target destinat...
Citations
... 68 To evaluate whether mouse INs can migrate within the human organoid hosts, we conducted live imaging of chimeric organoids at 1 DPG, capturing hourly observations for 24 h. Consistent with prior in vivo and in vitro studies, 69,70 we observed that mouse cells exhibited high migratory activity within the human cortical organoids. The grafted mouse cells displayed exploratory behavior, neurite branching, and nucleokinesis typical of migrating INs from the MGE ( Figure 3B). ...
... The slow access to the global workspace in the masking experiment explains the long duration of the attentional blink, in both cases around the second. This slowness reflects the protracted maturation of the parietal-frontal associative regions (Lebenberg et al., 2019), neuronal maturation (Gascoigne, Serdyukova, & Aksenov, 2021;Faux, Rakic, Andrews, & Britto, 2012), synaptogenesis and pruning (Huttenlocher & Dabholkar, 1997), and connectivity (Dubois, Hertz-Pannier, Dehaene-Lambertz, Cointepas, & Le Bihan, 2006). The protracted maturation of high-level areas contrasts with the faster maturation of the primary cortices. ...
Perceptual awareness in infants during the first year of life is understudied, despite the philosophical, scientific, and clinical importance of understanding how and when consciousness emerges during human brain development. Although parents are undoubtedly convinced that their infant is conscious, the lack of adequate experimental paradigms to address this question in preverbal infants has been a hindrance to research on this topic. However, recent behavioral and brain imaging studies have shown that infants are engaged in complex learning from an early age and that their brains are more structured than traditionally thought. I will present a rapid overview of these results, which might provide indirect evidence of early perceptual awareness and then describe how a more systematic approach to this question could stand within the framework of global workspace theory, which identifies specific signatures of conscious perception in adults. Relying on these brain signatures as a benchmark for conscious perception, we can deduce that it exists in the second half of the first year, whereas the evidence before the age of 5 months is less solid, mainly because of the paucity of studies. The question of conscious perception before term remains open, with the possibility of short periods of conscious perception, which would facilitate early learning. Advances in brain imaging and growing interest in this subject should enable us to gain a better understanding of this important issue in the years to come.
... During the development of the CNS, different neuron subtypes that assemble into a functional circuit are often born at various developmental time points (Faux et al., 2012). In order to find their respective synaptic partner, late-born neurons have the daunting task of extending their dendrites and axon into the correct layer (Faux et al., 2012). ...
... During the development of the CNS, different neuron subtypes that assemble into a functional circuit are often born at various developmental time points (Faux et al., 2012). In order to find their respective synaptic partner, late-born neurons have the daunting task of extending their dendrites and axon into the correct layer (Faux et al., 2012). However, the molecular mechanism of how late-born neurons know where to precisely extend their processes to form synapses with their respective targets remains poorly understood. ...
... We found loss of b II-spectrin disrupts the normal positioning of the dendrites of rod bipolar at early stages and this leads to defects in synaptic connectivity and impaired retinal responses in the adult. Throughout the CNS, neurons are integrated into a nascent neural circuit at various stages during development (Faux et al., 2012). Defects in neuron migration, targeting, and connectivity are often linked to neurodevelopmental disorders such as intellectual disability, epilepsy, and autism spectrum disorder (Bozzi et al., 2012;Moon and Wynshaw-Boris, 2013;Pan et al., 2019). ...
Neural circuit assembly is a multi-step process where synaptic partners are often born at distinct developmental stages, and yet they must find each other and form precise synaptic connections with one another. This developmental process often relies on late-born neurons extending their processes to the appropriate layer to find and make synaptic connections to their early-born targets. The molecular mechanism responsible for the integration of late-born neurons into an emerging neural circuit remains unclear. Here we uncovered a new role for the cytoskeletal protein βII-spectrin in properly positioning pre- and post-synaptic neurons to the developing synaptic layer. Loss of βII-spectrin disrupts retinal lamination, leads to synaptic connectivity defects, and results in impaired visual function in both male and female mice. Together, these findings highlight a new function of βII-spectrin in assembling neural circuits in the mouse outer retina.
SIGNFICANCE STATEMENT:
Neurons that assemble into a functional circuit are often integrated at different developmental time points. However, the molecular mechanism that guides the precise positioning of neuronal processes to the correct layer for synapse formation is relatively unknown. Here we show a new role for the cytoskeletal scaffolding protein, βII-spectrin in the developing retina. βII-spectrin is required to position pre- and post-synaptic neurons to the nascent synaptic layer in the mouse outer retina. Loss of βII-spectrin disrupts positioning of neuronal processes, alters synaptic connectivity, and impairs visual function.
... CGE-derived INs express the transcription factors Sp8, COUP-TF2, Prox1, and Pax6, resulting in IN subpopulations that closely overlap with the cardinal subgroup of VIP cells and other smaller cardinal subgroups (Pleasure et al., 2000;Xu et al., 2003;Butt et al., 2005;Lee et al., 2010;Miyoshi et al., 2015;Tremblay et al., 2016;Lim et al., 2018;Fishell and Kepecs, 2020). Upon their generation, postmitotic cortical INs migrate tangentially from the subpallium along the subventricular and marginal zone to the cortical plate, switch their migration pattern and travel radially into the developing cortical plate to finally reach their destination in the postnatal cortex (Faux et al., 2012;Wamsley and Fishell, 2017). Like IN generation and cardinal specification, migration and settling are complex processes regulated by an intricate network of various motogens, chemoattractants, transcription factors, and neurotransmitters (Marín and Rubenstein, 2001;De Marco García et al., 2011;Wamsley and Fishell, 2017;Lim et al., 2018). ...
Information processing within neuronal circuits relies on their proper development and a balanced interplay between principal and local inhibitory interneurons within those circuits. Gamma-aminobutyric acid (GABA)ergic inhibitory interneurons are a remarkably heterogeneous population, comprising subclasses based on their morphological, electrophysiological, and molecular features, with differential connectivity and activity patterns. microRNA (miRNA)-dependent post-transcriptional control of gene expression represents an important regulatory mechanism for neuronal development and plasticity. miRNAs are a large group of small non-coding RNAs (21–24 nucleotides) acting as negative regulators of mRNA translation and stability. However, while miRNA-dependent gene regulation in principal neurons has been described heretofore in several studies, an understanding of the role of miRNAs in inhibitory interneurons is only beginning to emerge. Recent research demonstrated that miRNAs are differentially expressed in interneuron subclasses, are vitally important for migration, maturation, and survival of interneurons during embryonic development and are crucial for cognitive function and memory formation. In this review, we discuss recent progress in understanding miRNA-dependent regulation of gene expression in interneuron development and function. We aim to shed light onto mechanisms by which miRNAs in GABAergic interneurons contribute to sculpting neuronal circuits, and how their dysregulation may underlie the emergence of numerous neurodevelopmental and neuropsychiatric disorders.
... In many other mouse models of disrupted laminar organization, inhibitory neurons are mislocalized to aberrant layers as a result of impairments in migration or disruptions in cell-fate specification during neurogenesis (Liodis et al., 2007;Vogt et al., 2014;Bartolini et al., 2017). Unlike their excitatory counterparts, cortical interneurons are born in the ventricular zones of ganglionic eminences of the embryonic brain and migrate tangentially in distinct migratory streams before migrating radially into the cortical plate (Pla et al., 2006;Lopez-Bendito et al., 2008;Faux et al., 2012), creating a window of high vulnerability for defective migration. Nep was shown to regulate the migration of prostatic cancer cells via inhibiting the phosphorylation of focal adhesion kinase (Sumitomo et al., 2000(Sumitomo et al., , 2004, and it is possible that Nep on migrating inhibitory neurons in the embryonic brain may guide their migration and laminar distribution. ...
Neprilysin (Nep) is a membrane-bound zinc-dependent endopeptidase that cleaves a wide variety of small peptides in the body. In the brain, it has gained fame as an important endogenous degrader of amyloid beta peptide, responsible for the pathophysiology of Alzheimer’s disease. Nep is expressed specifically by parvalbumin (PV)-expressing inhibitory neurons in the adult cortex, the maturation of which regulates critical period plasticity. Given that PV neuron soma and proximal dendrites are primary sites of perineuronal net (PNN) formation, we investigated the role that Nep plays in PNN and PV neuron maturation and cortical development in the mouse visual cortex, using mice whose Nep expression is constitutively knocked out (Nep KO mice). Nep expression is high in young wildtype mice (P10) and is downregulated rapidly throughout postnatal development. It is especially prominent in layer 5 where it is highly expressed by inhibitory neurons and also expressed at low levels by many excitatory neurons. Contrary to our hypothesis, Nep KO mice did not show an alteration in the relative density or gross morphology of PNNs. Instead, Nep KO mice showed reduced maximal activation of L5 after white matter stimulation and decreased number of inhibitory neurons in L4. These laminar defects may lead to impaired development of optomotor acuity in Nep KO mice.
... We manually curated current literature on interneuron development to short list genes expressed by interneurons (Wonders and Anderson 2006;Faux et al. 2012;Chen et al. 2017;Mayer et al. 2018;Mi et al. (which was not certified by peer review) is the author/funder. All rights reserved. ...
The cortical plate is composed of excitatory and inhibitory neurons, the latter of which originate in the ganglionic eminences. From their origin in the ventral telencephalon, interneuron precursors migrate during embryonic development over some distance to reach their final destination in the cortical plate. The histone methyltransferase DOT1L is necessary for proper cortical plate development and layer distribution of glutamatergic neurons, however, its specific role on cortical interneuron development has not yet been explored. Here, we demonstrate that DOT1L affects interneuron development in a cell-autonomous manner. Deletion of Dot1l in MGE-derived interneuron precursor cells results in an overall reduction and altered distribution of GABAergic interneurons in the cortical plate at postnatal day (P) 0. Furthermore, we observed an altered proportion of GABAergic interneurons in the cortex and striatum at P21 with a significant decrease in Parvalbumin (PVALB)-expressing interneurons. Altogether, our results indicate that reduced numbers of cortical interneurons upon DOT1L deletion results from altered post-mitotic differentiation/maturation.
... During normal brain development, neurons migrate from where they are produced to their destination; excitatory neurons produced in the VZ/SVZ around the lateral ventricles radially migrate toward the cortex through the IZ and SP to reach the CP. [27][28][29][30][31][32][33][34] Since the deep medullary veins, which develop from the ventricular side toward the cortex, are closely related to neuronal migration, 25 our findings that pre-CEL presence at and beyond 19 weeks and abnormal CEL are more common in the MCD group are convincing. Since there are varying degrees of neuronal migration impairment, it is not surprising that the presentation of pre-CELs and abnormal CELs in the MCD group is variable. ...
Objectives:
Diagonal echogenic lines outside the lateral ventricle have often been observed in the anterior coronal planes of the normal fetal brain by neurosonography. We have observed abnormal shapes of these echogenic lines in cases of malformation of cortical development (MCD). We named the ultrasound finding "cat-ear-line" (CEL). This study aimed to examine how and when CEL develops in normal cases compared with MCD cases.
Methods:
We retrospectively examined the fetal brain volume dataset acquired through transvaginal 3D neurosonography of 575 control cases and 39 MCD cases from 2014 to 2020. We defined CEL as the hyperechogenic continuous lines through subplate (SP) and intermediate zone (IZ), pre-CEL as the lines that existed only within the SP, and abnormal CEL as a mass-like or mosaic shadow-like structure that existed across the SP and IZ. All fetuses in the MCD group had some neurosonographic abnormalities and were ultimately diagnosed with MCD.
Results:
The CEL was detected in 97.9% (369/377) of the control group from 19 to 30 weeks. The CEL visualization rate of the MCD group in the same period was 40.0% (14/35) which was significantly lower than that of the control group (P < .001).
Conclusions:
From this study, it appears that the CEL is an ultrasound finding observed at and beyond 19 weeks in a normally developing fetus. In some MCD cases, pre-CEL at and beyond 19 weeks or abnormal CEL was observed. Maldeveloped CEL at mid-trimester may help identify cases at-risk of subsequent MCD.
... During the development of the central nervous system, different neuron subtypes 45 that assemble into a functional circuit are often born at various developmental time points 46 (Faux et al., 2012). In order to find their respective synaptic partner, late-born neurons 47 have the daunting task of extending their dendrites and axon into the correct layer (Faux 48 et al., 2012). ...
Neural circuit assembly is a multi-step process where synaptic partners are often born at distinct developmental stages, and yet they must find each other and form precise synaptic connections with one another. This developmental process often relies on late-born neurons extending their processes to the appropriate layer to find and make synaptic connections to their early-born targets. The molecular mechanism responsible for the integration of late-born neurons into an emerging neural circuit remains unclear. Here we uncovered a new role for the cytoskeletal protein βII-spectrin in properly positioning pre- and post-synaptic neurons to the developing synaptic layer. Loss of βII-spectrin disrupts retinal lamination, leads to synaptic connectivity defects, and results in impaired visual function. Together, these findings highlight a new function of βII-spectrin in assembling neural circuits in the mouse outer retina.
Highlights
Established a new role for βII-spectrin in assembling retinal circuits
βII-spectrin positions pre- and post-synaptic neurons to the developing synaptic layer
Early positioning of processes to the OPL is required for synaptogenesis
Loss of βII-spectrin disrupts synaptic connectivity and impairs visual function
... New rounds of asymmetric division, involving the generation of intermediate progenitors (indirect neurogenesis), produce the excitatory projection neurons. These neurons migrate along the shaft of the basal process of the radial glia, pass the subplate layer, and are positioned between the Cajal-Retzius cells and the subplate cells (Faux et al. 2012). This process is called preplate splitting and marks the origin of the cortical plate by GW8. ...
Brain development is critically dependent on the timely supply of thyroid hormones. The thyroid hormone transporters are central to the action of thyroid hormones in the brain, facilitating their passage through the blood-brain barrier. Mutations of the monocarboxylate transporter 8 (MCT8) cause the Allan-Herndon-Dudley syndrome, with altered thyroid hormone concentrations in blood and profound neurological impairment and intellectual deficit. Mouse disease models have revealed interplay between transport, deiodination, and availability of T3 to receptors in specific cells. However, the mouse models are not satisfactory given the fundamental differences between the mouse and human brains. The goal of the present work is to review human neocortex development in the context of thyroid pathophysiology. Recent developments in single-cell transcriptomic approaches aimed at the human brain make it possible to profile the expression of thyroid hormone regulators in single-cell RNA-Seq datasets of the developing human neocortex. The data provide novel insights into the specific cellular expression of thyroid hormone transporters, deiodinases, and receptors.
... Again, fine signaling is required for the different phases of migration, with Reelin being the most relevant to control different phases of this migratory activity (Trommsdorff et al., 1999;Kuo et al., 2005;Hirota and Nakajima, 2017). To complete cortex formation, inhibitory interneurons from the ventral telencephalon (the transient ganglionic eminences in humans) migrate long-range moving tangentially to the RG fibers to reach their final correct position and connect with other neurons in the CP (Lavdas et al., 1999;Bellion et al., 2005;Miyoshi et al., 2010;Faux et al., 2012;Barber and Pierani, 2016; Table 1). Their peculiar saltatory migration behavior, characterized by pauses in between fast periods of movement, is obtained via microtubules-dependent nuclear translocation (Bellion et al., 2005;Silva et al., 2018). ...
The variety in the display of animals’ cognition, emotions, and behaviors, typical of humans, has its roots within the anterior-most part of the brain: the forebrain, giving rise to the neocortex in mammals. Our understanding of cellular and molecular events instructing the development of this domain and its multiple adaptations within the vertebrate lineage has progressed in the last decade. Expanding and detailing the available knowledge on regionalization, progenitors’ behavior and functional sophistication of the forebrain derivatives is also key to generating informative models to improve our characterization of heterogeneous and mechanistically unexplored cortical malformations. Classical and emerging mammalian models are irreplaceable to accurately elucidate mechanisms of stem cells expansion and impairments of cortex development. Nevertheless, alternative systems, allowing a considerable reduction of the burden associated with animal experimentation, are gaining popularity to dissect basic strategies of neural stem cells biology and morphogenesis in health and disease and to speed up preclinical drug testing. Teleost vertebrates such as zebrafish, showing conserved core programs of forebrain development, together with patients-derived in vitro 2D and 3D models, recapitulating more accurately human neurogenesis, are now accepted within translational workflows spanning from genetic analysis to functional investigation. Here, we review the current knowledge of common and divergent mechanisms shaping the forebrain in vertebrates, and causing cortical malformations in humans. We next address the utility, benefits and limitations of whole-brain/organism-based fish models or neuronal ensembles in vitro for translational research to unravel key genes and pathological mechanisms involved in neurodevelopmental diseases.
