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In this issue of Cell, Gouwens et al. establish the state of the art for defining inhibitory cell types in the mouse neocortex. By combining morphological, electrophysiological, and transcriptomic features to classify interneurons in the mouse visual cortex, this work provides a roadmap for understanding the diversity of cell types and their functional role in cortical computations.
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Neocórtex , Transcriptoma , Animais , Fenômenos Eletrofisiológicos , Interneurônios , CamundongosRESUMO
GABAergic inhibition plays an important role in the establishment and maintenance of cortical circuits during development. Neuregulin 1 (Nrg1) and its interneuron-specific receptor ErbB4 are key elements of a signaling pathway critical for the maturation and proper synaptic connectivity of interneurons. Using conditional deletions of the ERBB4 gene in mice, we tested the role of this signaling pathway at two developmental timepoints in parvalbumin-expressing (PV) interneurons, the largest subpopulation of cortical GABAergic cells. Loss of ErbB4 in PV interneurons during embryonic, but not late postnatal development leads to alterations in the activity of excitatory and inhibitory cortical neurons, along with severe disruption of cortical temporal organization. These impairments emerge by the end of the second postnatal week, prior to the complete maturation of the PV interneurons themselves. Early loss of ErbB4 in PV interneurons also results in profound dysregulation of excitatory pyramidal neuron dendritic architecture and a redistribution of spine density at the apical dendritic tuft. In association with these deficits, excitatory cortical neurons exhibit normal tuning for sensory inputs, but a loss of state-dependent modulation of the gain of sensory responses. Together these data support a key role for early developmental Nrg1/ErbB4 signaling in PV interneurons as a powerful mechanism underlying the maturation of both the inhibitory and excitatory components of cortical circuits.
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Células Piramidais , Transdução de Sinais , Animais , Camundongos , Interneurônios/metabolismo , Neuregulina-1/metabolismo , Neurônios/metabolismo , Parvalbuminas/metabolismo , Células Piramidais/metabolismo , Receptor ErbB-4/genéticaRESUMO
Diverse subsets of cortical interneurons have vital roles in higher-order brain functions. To investigate how this diversity is generated, here we used single-cell RNA sequencing to profile the transcriptomes of mouse cells collected along a developmental time course. Heterogeneity within mitotic progenitors in the ganglionic eminences is driven by a highly conserved maturation trajectory, alongside eminence-specific transcription factor expression that seeds the emergence of later diversity. Upon becoming postmitotic, progenitors diverge and differentiate into transcriptionally distinct states, including an interneuron precursor state. By integrating datasets across developmental time points, we identified shared sources of transcriptomic heterogeneity between adult interneurons and their precursors, and uncovered the embryonic emergence of cardinal interneuron subtypes. Our analysis revealed that the transcription factor Mef2c, which is linked to various neuropsychiatric and neurodevelopmental disorders, delineates early precursors of parvalbumin-expressing neurons, and is essential for their development. These findings shed new light on the molecular diversification of early inhibitory precursors, and identify gene modules that may influence the specification of human interneuron subtypes.
Assuntos
Diferenciação Celular , Interneurônios/citologia , Interneurônios/fisiologia , Inibição Neural , Córtex Visual/citologia , Animais , Diferenciação Celular/genética , Embrião de Mamíferos/citologia , Feminino , Gânglios/citologia , Gânglios/metabolismo , Perfilação da Expressão Gênica , Humanos , Fatores de Transcrição MEF2/metabolismo , Masculino , Camundongos , Mitose/genética , Parvalbuminas/metabolismo , RNA Citoplasmático Pequeno/genética , Análise de Célula ÚnicaRESUMO
Cortical parvalbumin-expressing (Pvalb+) neurons provide robust inhibition to neighboring pyramidal neurons, crucial for the proper functioning of cortical networks. This class of inhibitory neurons undergoes extensive synaptic formation and maturation during the first weeks after birth and continue to dynamically maintain their synaptic output throughout adulthood. While several transcription factors, such as Nkx2-1, Lhx6, and Sox6, are known to be necessary for the differentiation of progenitors into Pvalb+ neurons, which transcriptional programs underlie the postnatal maturation and maintenance of Pvalb+ neurons' innervation and synaptic function remains largely unknown. Because Sox6 is continuously expressed in Pvalb+ neurons until adulthood, we used conditional knock-out strategies to investigate its putative role in the postnatal maturation and synaptic function of cortical Pvalb+ neurons in mice of both sexes. We found that early postnatal loss of Sox6 in Pvalb+ neurons leads to failure of synaptic bouton growth, whereas later removal in mature Pvalb+ neurons in the adult causes shrinkage of already established synaptic boutons. Paired recordings between Pvalb+ neurons and pyramidal neurons revealed reduced release probability and increased failure rate of Pvalb+ neurons' synaptic output. Furthermore, Pvalb+ neurons lacking Sox6 display reduced expression of full-length tropomyosin-receptor kinase B (TrkB), a key modulator of GABAergic transmission. Once re-expressed in neurons lacking Sox6, TrkB was sufficient to rescue the morphologic synaptic phenotype. Finally, we showed that Sox6 mRNA levels were increased by motor training. Our data thus suggest a constitutive role for Sox6 in the maintenance of synaptic output from Pvalb+ neurons into adulthood.SIGNIFICANCE STATEMENT Cortical parvalbumin-expressing (Pvalb+) inhibitory neurons provide robust inhibition to neighboring pyramidal neurons, crucial for the proper functioning of cortical networks. These inhibitory neurons undergo extensive synaptic formation and maturation during the first weeks after birth and continue to dynamically maintain their synaptic output throughout adulthood. However, it remains largely unknown which transcriptional programs underlie the postnatal maturation and maintenance of Pvalb+ neurons. Here, we show that the transcription factor Sox6 cell-autonomously regulates the synaptic maintenance and output of Pvalb+ neurons until adulthood, leaving unaffected other maturational features of this neuronal population.
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Córtex Cerebral/metabolismo , Neurônios/metabolismo , Parvalbuminas/biossíntese , Fatores de Transcrição SOXD/biossíntese , Sinapses/metabolismo , Animais , Animais Recém-Nascidos , Córtex Cerebral/citologia , Feminino , Técnicas de Introdução de Genes , Masculino , Camundongos , Camundongos Transgênicos , Técnicas de Cultura de Órgãos , Parvalbuminas/genética , Fatores de Transcrição SOXD/genética , Sinapses/genéticaRESUMO
Complex and precisely orchestrated genetic programs contribute to the generation, migration, and maturation of cortical GABAergic interneurons (cIN). Yet, little is known about the signals that mediate the rapid alterations in gene expression that are required for cINs to transit through a series of developmental steps leading to their mature properties in the cortex. Here, we investigated the function of post-transcriptional regulation of gene expression by microRNAs on the development of cIN precursors. We find that conditional removal of the RNAseIII enzyme Dicer reduces the number of cINs in the adult mouse. Dicer is further necessary for the morphological and molecular maturation of cINs. Loss of mature miRNAs affects cINs development by impairing migration and differentiation of this cell type, while leaving proliferation of progenitors unperturbed. These developmental defects closely matched the abnormal expression of molecules involved in apoptosis and neuronal specification. In addition, we identified several miRNAs that are selectively upregulated in the postmitotic cINs, consistent with a role of miRNAs in the post-transcriptional control of the differentiation and apoptotic programs essential for cIN maturation. Thus, our results indicate that cIN progenitors require Dicer-dependent mechanisms to fine-tune the migration and maturation of cINs.
Assuntos
Sobrevivência Celular/fisiologia , Córtex Cerebral/fisiologia , RNA Helicases DEAD-box/metabolismo , Neurônios GABAérgicos/fisiologia , Interneurônios/fisiologia , MicroRNAs/metabolismo , Ribonuclease III/metabolismo , Animais , Apoptose/fisiologia , Contagem de Células , Proliferação de Células/fisiologia , Córtex Cerebral/crescimento & desenvolvimento , RNA Helicases DEAD-box/genética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células-Tronco Neurais/fisiologia , Proteínas Nucleares/metabolismo , Ribonuclease III/genética , Fator Nuclear 1 de Tireoide , Fatores de Transcrição/metabolismoRESUMO
High-dimensional data have become ubiquitous in the biological sciences, and it is often desirable to compare two datasets collected under different experimental conditions to extract low-dimensional patterns enriched in one condition. However, traditional dimensionality reduction techniques cannot accomplish this because they operate on only one dataset. Contrastive principal component analysis (cPCA) has been proposed to address this problem, but it has seen little adoption because it requires tuning a hyperparameter resulting in multiple solutions, with no way of knowing which is correct. Moreover, cPCA uses foreground and background conditions that are treated differently, making it ill-suited to compare two experimental conditions symmetrically. Here we describe the development of generalized contrastive PCA (gcPCA), a flexible hyperparameter-free approach that solves these problems. We first provide analyses explaining why cPCA requires a hyperparameter and how gcPCA avoids this requirement. We then describe an open-source gcPCA toolbox containing Python and MATLAB implementations of several variants of gcPCA tailored for different scenarios. Finally, we demonstrate the utility of gcPCA in analyzing diverse high-dimensional biological data, revealing unsupervised detection of hippocampal replay in neurophysiological recordings and heterogeneity of type II diabetes in single-cell RNA sequencing data. As a fast, robust, and easy-to-use comparison method, gcPCA provides a valuable resource facilitating the analysis of diverse high-dimensional datasets to gain new insights into complex biological phenomena.
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BACKGROUND: MEF2C is strongly linked to various neurodevelopmental disorders including autism, intellectual disability, schizophrenia, and attention-deficit/hyperactivity disorder. Mice that constitutively lack 1 copy of Mef2c or selectively lack both copies of Mef2c in cortical excitatory neurons display a variety of behavioral phenotypes associated with neurodevelopmental disorders. The MEF2C protein is a transcription factor necessary for cellular development and synaptic modulation of excitatory neurons. MEF2C is also expressed in a subset of cortical GABAergic (gamma-aminobutyric acidergic) inhibitory neurons, but its function in those cell types remains largely unknown. METHODS: Using conditional deletions of the Mef2c gene in mice, we investigated the role of MEF2C in parvalbumin-expressing interneurons (PV-INs), the largest subpopulation of cortical GABAergic cells, at 2 developmental time points. We performed slice electrophysiology, in vivo recordings, and behavior assays to test how embryonic and late postnatal loss of MEF2C from GABAergic INs impacts their survival and maturation and alters brain function and behavior. RESULTS: Loss of MEF2C from PV-INs during embryonic, but not late postnatal, development resulted in reduced PV-IN number and failure of PV-INs to molecularly and synaptically mature. In association with these deficits, early loss of MEF2C in GABAergic INs led to abnormal cortical network activity, hyperactive and stereotypic behavior, and impaired cognitive and social behavior. CONCLUSIONS: MEF2C expression is critical for the development of cortical GABAergic INs, particularly PV-INs. Embryonic loss of function of MEF2C mediates dysfunction of GABAergic INs, leading to altered in vivo patterns of cortical activity and behavioral phenotypes associated with neurodevelopmental disorders.
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MEF2C is strongly linked to various neurodevelopmental disorders (NDDs) including autism, intellectual disability, schizophrenia, and attention-deficit/hyperactivity. Mice constitutively lacking one copy of Mef2c , or selectively lacking both copies of Mef2c in cortical excitatory neurons, display a variety of behavioral phenotypes associated with NDDs. The MEF2C protein is a transcription factor necessary for cellular development and synaptic modulation of excitatory neurons. MEF2C is also expressed in a subset of cortical GABAergic inhibitory neurons, but its function in those cell types remains largely unknown. Using conditional deletions of the Mef2c gene in mice, we investigated the role of MEF2C in Parvalbumin-expressing Interneurons (PV-INs), the largest subpopulation of cortical GABAergic cells, at two developmental timepoints. We performed slice electrophysiology, in vivo recordings, and behavior assays to test how embryonic and late postnatal loss of MEF2C from GABAergic interneurons impacts their survival and maturation, and alters brain function and behavior. We found that loss of MEF2C from PV-INs during embryonic, but not late postnatal, development resulted in reduced PV-IN number and failure of PV-INs to molecularly and synaptically mature. In association with these deficits, early loss of MEF2C in GABAergic interneurons lead to abnormal cortical network activity, hyperactive and stereotypic behavior, and impaired cognitive and social behavior. Our findings indicate that MEF2C expression is critical for the development of cortical GABAergic interneurons, particularly PV-INs. Embryonic loss of function of MEF2C mediates dysfunction of GABAergic interneurons, leading to altered in vivo patterns of cortical activity and behavioral phenotypes associated with neurodevelopmental disorders.
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Retinal waves represent an early form of patterned spontaneous neural activity in the visual system. These waves originate in the retina before eye-opening and propagate throughout the visual system, influencing the assembly and maturation of subcortical visual brain regions. However, because it is technically challenging to ablate retina-derived cortical waves without inducing compensatory activity, the role these waves play in the development of the visual cortex remains unclear. To address this question, we used targeted conditional genetics to disrupt cholinergic retinal waves and their propagation to select regions of primary visual cortex, which largely prevented compensatory patterned activity. We find that loss of cholinergic retinal waves without compensation impaired the molecular and synaptic maturation of excitatory neurons located in the input layers of visual cortex, as well as layer 1 interneurons. These perinatal molecular and synaptic deficits also relate to functional changes observed at later ages. We find that the loss of perinatal cholinergic retinal waves causes abnormal visual cortex retinotopy, mirroring changes in the retinotopic organization of gene expression, and additionally impairs the processing of visual information. We further show that retinal waves are necessary for higher order processing of sensory information by impacting the state-dependent activity of layer 1 interneurons, a neuronal type that shapes neocortical state-modulation, as well as for state-dependent gain modulation of visual responses of excitatory neurons. Together, these results demonstrate that a brief targeted perinatal disruption of patterned spontaneous activity alters early cortical gene expression as well as synaptic and physiological development, and compromises both fundamental and, notably, higher-order functions of visual cortex after eye-opening.
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Behavioral states such as sleep and wake are highly correlated with specific patterns of rhythmic activity in the cortex. During low arousal states such as slow wave sleep, the cortex is synchronized and dominated by low frequency rhythms coordinated across multiple regions. Although recent evidence suggests that GABAergic inhibitory neurons are key players in cortical state modulation, the in vivo circuit mechanisms coordinating synchronized activity among local and distant neocortical networks are not well understood. Here, we show that somatostatin and chondrolectin co-expressing cells (Sst-Chodl cells), a sparse and unique class of neocortical inhibitory neurons, are selectively active during low arousal states and are largely silent during periods of high arousal. In contrast to other neocortical inhibitory neurons, we show these neurons have long-range axons that project across neocortical areas. Activation of Sst-Chodl cells is sufficient to promote synchronized cortical states characteristic of low arousal, with increased spike co-firing and low frequency brain rhythms, and to alter behavioral states by promoting sleep. Contrary to the prevailing belief that sleep is exclusively driven by subcortical mechanisms, our findings reveal that these long-range inhibitory neurons not only track changes in behavioral state but are sufficient to induce both sleep-like cortical states and sleep behavior, establishing a crucial circuit component in regulating behavioral states.
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Although previous work identified transcription factors crucial for the specification and migration of parvalbumin (PV)-expressing and somatostatin (SST)-expressing interneurons, the intrinsic factors required for the terminal differentiation, connectivity, and survival of these cell types remain uncharacterized. Here we demonstrate that, within subpopulations of cortical interneurons, Satb1 (special AT-rich binding protein) promotes terminal differentiation, connectivity, and survival in interneurons that express PV and SST. We find that conditional removal of Satb1 in mouse interneurons results in the loss of a majority of SST-expressing cells across all cortical layers, as well as some PV-expressing cells in layers IV and VI, by postnatal day 21. SST-expressing cells initially migrate to the cortex in Satb1 mutant mice, but receive reduced levels of afferent input and begin to die during the first postnatal week. Electrophysiological characterization indicates that loss of Satb1 function in interneurons results in a loss of functional inhibition of excitatory principal cells. These data suggest that Satb1 is required for medial ganglionic eminence-derived interneuron differentiation, connectivity, and survival.
Assuntos
Diferenciação Celular/fisiologia , Córtex Cerebral/crescimento & desenvolvimento , Interneurônios/fisiologia , Proteínas de Ligação à Região de Interação com a Matriz/fisiologia , Terminações Pré-Sinápticas/fisiologia , Animais , Ondas Encefálicas/fisiologia , Movimento Celular/fisiologia , Sobrevivência Celular/fisiologia , Córtex Cerebral/citologia , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Interneurônios/citologia , Interneurônios/metabolismo , Proteínas de Ligação à Região de Interação com a Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibição Neural/fisiologia , Parvalbuminas/metabolismo , Terminações Pré-Sinápticas/metabolismo , Somatostatina/metabolismo , Fatores de Transcrição/metabolismo , Fatores de Transcrição/fisiologiaRESUMO
Recent progress in cortical stem cell transplantation has demonstrated its potential to repair the brain. However, current transplant models have yet to demonstrate that the circuitry of transplant-derived neurons can encode useful function to the host. This is likely due to missing cell types within the grafts, abnormal proportions of cell types, abnormal cytoarchitecture, and inefficient vascularization. Here, we devised a transplant platform for testing neocortical tissue prototypes. Dissociated mouse embryonic telencephalic cells in a liquid scaffold were transplanted into aspiration-lesioned adult mouse cortices. The donor neuronal precursors differentiated into upper and deep layer neurons that exhibited synaptic puncta, projected outside of the graft to appropriate brain areas, became electrophysiologically active within one month post-transplant, and responded to visual stimuli. Interneurons and oligodendrocytes were present at normal densities in grafts. Grafts became fully vascularized by one week post-transplant and vessels in grafts were perfused with blood. With this paradigm, we could also organize cells into layers. Overall, we have provided proof of a concept for an in vivo platform that can be used for developing and testing neocortical-like tissue prototypes.
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Although cardinal cortical interneuron identity is established upon cell-cycle exit, it remains unclear whether specific interneuron subtypes are pre-established, and if so, how their identity is maintained prior to circuit integration. We conditionally removed Sox6 (Sox6-cKO) in migrating somatostatin (Sst+) interneurons and assessed the effects on their mature identity. In adolescent mice, five of eight molecular Sst+ subtypes were nearly absent in the Sox6-cKO cortex without a reduction in cell number. Sox6-cKO cells displayed electrophysiological maturity and expressed genes enriched within the broad class of Sst+ interneurons. Furthermore, we could infer subtype identity prior to cortical integration (embryonic day 18.5), suggesting that the loss in subtype was due to disrupted subtype maintenance. Conversely, Sox6 removal at postnatal day 7 did not disrupt marker expression in the mature cortex. Therefore, Sox6 is necessary during migration for maintenance of Sst+ subtype identity, indicating that subtype maintenance requires active transcriptional programs.
Assuntos
Interneurônios , Somatostatina , Camundongos , Animais , Interneurônios/fisiologia , Somatostatina/metabolismo , Fenômenos Eletrofisiológicos , Córtex Cerebral , Parvalbuminas/metabolismoRESUMO
Rett Syndrome is a devastating neurodevelopmental disorder resulting from mutations in the gene MECP2. Mutations of Mecp2 that are restricted to GABAergic cell types largely replicate the behavioral phenotypes associated with mouse models of Rett Syndrome, suggesting a pathophysiological role for inhibitory interneurons. Recent work has suggested that vasoactive intestinal peptide-expressing (VIP) interneurons may play a critical role in the proper development and function of cortical circuits, making them a potential key point of vulnerability in neurodevelopmental disorders. However, little is known about the role of VIP interneurons in Rett Syndrome. Here we find that loss of MeCP2 specifically from VIP interneurons replicates key neural and behavioral phenotypes observed following global Mecp2 loss of function.
Assuntos
Interneurônios/fisiologia , Proteína 2 de Ligação a Metil-CpG/metabolismo , Síndrome de Rett/genética , Peptídeo Intestinal Vasoativo/metabolismo , Animais , Modelos Animais de Doenças , Neurônios GABAérgicos/fisiologia , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos Transgênicos , Síndrome de Rett/fisiopatologiaRESUMO
Recent success in identifying gene-regulatory elements in the context of recombinant adeno-associated virus vectors has enabled cell-type-restricted gene expression. However, within the cerebral cortex these tools are largely limited to broad classes of neurons. To overcome this limitation, we developed a strategy that led to the identification of multiple new enhancers to target functionally distinct neuronal subtypes. By investigating the regulatory landscape of the disease gene Scn1a, we discovered enhancers selective for parvalbumin (PV) and vasoactive intestinal peptide-expressing interneurons. Demonstrating the functional utility of these elements, we show that the PV-specific enhancer allowed for the selective targeting and manipulation of these neurons across vertebrate species, including humans. Finally, we demonstrate that our selection method is generalizable and characterizes additional PV-specific enhancers with exquisite specificity within distinct brain regions. Altogether, these viral tools can be used for cell-type-specific circuit manipulation and hold considerable promise for use in therapeutic interventions.
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Dependovirus/genética , Vetores Genéticos/genética , Interneurônios/fisiologia , Animais , Callithrix , Córtex Cerebral/citologia , Feminino , Humanos , Macaca mulatta , Camundongos , Camundongos Endogâmicos C57BL , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Neurônios , Parvalbuminas/fisiologia , Ratos , Ratos Sprague-Dawley , Especificidade da Espécie , Peptídeo Intestinal Vasoativo/fisiologiaRESUMO
Olfactory bulb (OB) interneurons are a heterogeneous population produced beginning in embryogenesis and continuing through adulthood. Understanding how this diversity arises will provide insight into how OB microcircuitry is established as well as adult neurogenesis. Particular spatial domains have been shown to contribute specific interneuron subtypes. However, the temporal profile by which OB interneuron subtypes are produced is unknown. Using inducible genetic fate mapping of Dlx1/2 precursors, we analyzed the production of seven OB interneuron subtypes and found that the generation of each subpopulation has a unique temporal signature. Within the glomerular layer, the production of tyrosine hydroxylase-positive interneurons is maximal during early embryogenesis and decreases thereafter. In contrast, the generation of calbindin interneurons is maximal during late embryogenesis and declines postnatally, whereas calretinin (CR) cell production is low during embryogenesis and increases postnatally. Parvalbumin interneurons within the external plexiform layer are produced only perinatally, whereas the generation of 5T4-positive granule cells in the mitral cell layer does not change significantly over time. CR-positive granule cells are not produced at early embryonic time points, but constitute a large percentage of the granule cells born after birth. Blanes cells in contrast are produced in greatest number during embryogenesis. Together we provide the first comprehensive analysis of the temporal generation of OB interneuron subtypes and demonstrate that the timing by which these populations are produced is tightly orchestrated.
Assuntos
Diferenciação Celular , Interneurônios/classificação , Interneurônios/citologia , Bulbo Olfatório/citologia , Envelhecimento/fisiologia , Animais , Animais Recém-Nascidos , Embrião de Mamíferos/citologia , Desenvolvimento Embrionário , Feminino , Interneurônios/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Bulbo Olfatório/embriologia , Bulbo Olfatório/crescimento & desenvolvimento , Bulbo Olfatório/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Fatores de TempoRESUMO
At present little is known about the developmental mechanisms that give rise to inhibitory gamma-aminobutyric acidergic interneurons of the neocortex or the timing of their subtype specification. As such, we performed a gene expression microarray analysis on cortical interneuron precursors isolated through their expression of a Dlx5/6(Cre-IRES-EGFP) transgene. We purified these precursors from the embryonic mouse neocortex at E13.5 and E15.5 by sorting of enhanced green fluorescent protein-expressing cells. We identified novel transcription factors, neuropeptides, and cell surface genes whose expression is highly enriched in embryonic cortical interneuron precursors. Our identification of many of the genes known to be selectively enriched within cortical interneurons validated the efficacy of our approach. Surprisingly, we find that subpopulations of migrating cortical interneurons express genes encoding for proteins characteristic of mature interneuron subtypes as early as E13.5. These results provide support for the idea that many of the genes characteristic of specific cortical interneuron subtypes are evident prior to their functional integration into cortical microcircuitry. They suggest interneurons are already relegated to specific genetic subtypes shortly after they become postmitotic. Moreover, our work has revealed that many of the genes expressed in cortical interneuron precursors have been independently linked to neurological disorders in both mice and humans.
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Córtex Cerebral/citologia , Córtex Cerebral/embriologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Interneurônios/fisiologia , Células-Tronco/fisiologia , Animais , Proteínas de Ligação ao Cálcio/genética , Movimento Celular/fisiologia , Feminino , Proteínas de Fluorescência Verde/genética , Proteínas de Homeodomínio/genética , Interneurônios/citologia , Camundongos , Camundongos Transgênicos , Neuropeptídeos/genética , Análise de Sequência com Séries de Oligonucleotídeos , Gravidez , Receptores de GABA/genética , Células-Tronco/citologia , Sinapses/fisiologia , Fatores de Transcrição/genéticaRESUMO
In this issue, Wester et al. (2019) examine the obligate relationship between cortical interneurons and pyramidal neurons. By genetically converting superficial IT pyramidal cells into PT-like deep-layer pyramidal cells, they alter the position, connectivity, and gene expression within CGE-derived interneurons.
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Neocórtex , Interneurônios , Células PiramidaisRESUMO
In this review, we explore how contextual modulations of sensory processing are implemented within the local cortical circuit. We focus on contextual influences of global arousal state (e.g. how alert am I?), sensory predictions (e.g. which stimuli do I expect?), and top-down attention (what is relevant to me?). We review recent literature suggesting that these operations are implemented throughout sensory cortices, and are mediated by excitatory and inhibitory local circuits. By focusing on the circuit mechanisms of contextual modulation operations, we may begin to understand how mutations in GABAergic interneurons and alterations in neuromodulatory signaling lead to specific deficits of information processing in neuropsychiatric disease.
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Nível de Alerta/fisiologia , Neurônios GABAérgicos/fisiologia , Interneurônios/fisiologia , Rede Nervosa/fisiologia , Vias Neurais/fisiologia , Córtex Sensório-Motor/fisiologia , Animais , Neurônios GABAérgicos/metabolismo , Humanos , Interneurônios/metabolismo , Rede Nervosa/metabolismo , Vias Neurais/metabolismo , Córtex Sensório-Motor/metabolismoRESUMO
GABAergic interneurons play important roles in cortical circuit development. However, there are multiple populations of interneurons and their respective developmental contributions remain poorly explored. Neuregulin 1 (NRG1) and its interneuron-specific receptor ERBB4 are critical genes for interneuron maturation. Using a conditional ErbB4 deletion, we tested the role of vasoactive intestinal peptide (VIP)-expressing interneurons in the postnatal maturation of cortical circuits in vivo. ErbB4 removal from VIP interneurons during development leads to changes in their activity, along with severe dysregulation of cortical temporal organization and state dependence. These alterations emerge during adolescence, and mature animals in which VIP interneurons lack ErbB4 exhibit reduced cortical responses to sensory stimuli and impaired sensory learning. Our data support a key role for VIP interneurons in cortical circuit development and suggest a possible contribution to pathophysiology in neurodevelopmental disorders. These findings provide a new perspective on the role of GABAergic interneuron diversity in cortical development. VIDEO ABSTRACT.