Origin, Development, and Synaptogenesis of Cortical Interneurons

Llorca, Alfredo; Deogracias, Rubén

doi:10.3389/fnins.2022.929469

Cited by 20 publications

(23 citation statements)

References 217 publications

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“…Studies of neurogenesis within the fetal MIA brain have mostly focused on the pallium ( De Miranda et al, 2010 ; Gallagher et al, 2013 ; Braun et al, 2019 ; Canales et al, 2021 ), which is the main source of excitatory neurons within the cerebral cortex ( Llorca and Deogracias, 2022 ). Yet, inhibitory interneurons, which are repeatedly reported to be affected following MIA and in NDDs ( Nakamura et al, 2021 ; Yang et al, 2022 ; Yu et al, 2022 ), are predominantly derived from sub-pallial regions such as the caudal and medial ganglionic eminences as well as the preoptic area ( Yang et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

The impact of maternal immune activation on embryonic brain development

2023

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The adult brain is a complex structure with distinct functional sub-regions, which are generated from an initial pool of neural epithelial cells within the embryo. This transition requires a number of highly coordinated processes, including neurogenesis, i.e., the generation of neurons, and neuronal migration. These take place during a critical period of development, during which the brain is particularly susceptible to environmental insults. Neurogenesis defects have been associated with the pathogenesis of neurodevelopmental disorders (NDDs), such as autism spectrum disorder and schizophrenia. However, these disorders have highly complex multifactorial etiologies, and hence the underlying mechanisms leading to aberrant neurogenesis continue to be the focus of a significant research effort and have yet to be established. Evidence from epidemiological studies suggests that exposure to maternal infection in utero is a critical risk factor for NDDs. To establish the biological mechanisms linking maternal immune activation (MIA) and altered neurodevelopment, animal models have been developed that allow experimental manipulation and investigation of different developmental stages of brain development following exposure to MIA. Here, we review the changes to embryonic brain development focusing on neurogenesis, neuronal migration and cortical lamination, following MIA. Across published studies, we found evidence for an acute proliferation defect in the embryonic MIA brain, which, in most cases, is linked to an acceleration in neurogenesis, demonstrated by an increased proportion of neurogenic to proliferative divisions. This is accompanied by disrupted cortical lamination, particularly in the density of deep layer neurons, which may be a consequence of the premature neurogenic shift. Although many aspects of the underlying pathways remain unclear, an altered epigenome and mitochondrial dysfunction are likely mechanisms underpinning disrupted neurogenesis in the MIA model. Further research is necessary to delineate the causative pathways responsible for the variation in neurogenesis phenotype following MIA, which are likely due to differences in timing of MIA induction as well as sex-dependent variation. This will help to better understand the underlying pathogenesis of NDDs, and establish therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

The impact of maternal immune activation on embryonic brain development

2023

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“…However, the frequency of the mIPSCs in the NCAN ΔELS mutant mice was significantly reduced (~35%) compared to WT littermates (Figure 7T). In vivo, SST+ synapses are formed mostly on the distal dendrites of pyramidal neurons, while PV+ synapses are formed mainly on the neuronal soma (perisomatic) 61,62 . We analyzed the recording data to determine if the reduction in mIPSC frequency in the mutant mice is due to the loss of perisomatic or distal dendritic synaptic events.…”

Section: Ncan C-terminal Controls Sst Synapse Formation and Functionmentioning

confidence: 99%

Astrocyte-Secreted Neurocan Controls Inhibitory Synapse Formation and Function

Irala

Wang

Sakers

et al. 2023

Preprint

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Astrocytes strongly promote the formation and maturation of synapses by secreted proteins. To date, several astrocyte-secreted synaptogenic proteins controlling different stages of excitatory synapse development have been identified. However, the identities of astrocytic signals that induce inhibitory synapse formation remain elusive. Here, through a combination of in vitro and in vivo experiments, we identified Neurocan as an astrocyte-secreted inhibitory synaptogenic protein. Neurocan is a chondroitin sulfate proteoglycan that is best known as a protein localized to the perineuronal nets. However, Neurocan is cleaved into two after secretion from astrocytes. We found that the resulting N- and C- terminal fragments have distinct localizations in the extracellular matrix. While the N-terminal fragment remains associated with perineuronal nets, the Neurocan C-terminal fragment localizes to synapses and specifically controls cortical inhibitory synapse formation and function. Neurocan knockout mice lacking the whole protein or only its C-terminal synaptogenic region have reduced inhibitory synapse numbers and function. Through super-resolution microscopy and in vivo proximity labeling by secreted TurboID, we discovered that the synaptogenic domain of Neurocan localizes to somatostatin-positive inhibitory synapses and strongly regulates their formation. Together, our results unveil a mechanism through which astrocytes control circuit-specific inhibitory synapse development in the mammalian brain.

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“…The second most abundant SST-expressing cINs (accounting for ~30% INs) consist of two main types: 'Martinotti cells' that inhibit the distal dendrites of PNs or target other INs, and non-Martinotti cells that are present all cortical layers and extend their axons locally 4,8 . Thirdly, 5HTR3a INs (accounting ~30% INs) constitutes a diverse group of cell types with different laminar distribution, morphologies, functional properties, and connectivity patterns, e.g., vasointestinal peptide (VIP) expressing bipolar cells 4,8 . Furthermore, recent advances in single cell transcriptomics led to the identification of more than 50 subtypes of INs in mouse visual cortex based on transcriptomic signature and unbiased statistical classification 9 .…”

Section: Introductionmentioning

confidence: 99%

“…The most abundant cINs (accounting for ~40% INs) expressing PV (PV INs), for instance, can be divided into 'basket cells' targeting the soma of excitatory cells, and 'chandelier cells' innervating the axon initial segment. The second most abundant SST-expressing cINs (accounting for ~30% INs) consist of two main types: 'Martinotti cells' that inhibit the distal dendrites of PNs or target other INs, and non-Martinotti cells that are present all cortical layers and extend their axons locally 4,8 . Thirdly, 5HTR3a INs (accounting ~30% INs) constitutes a diverse group of cell types with different laminar distribution, morphologies, functional properties, and connectivity patterns, e.g., vasointestinal peptide (VIP) expressing bipolar cells 4,8 .…”

Section: Introductionmentioning

confidence: 99%

ARX regulates cortical interneuron differentiation and migration

Lim,

Akula,

Myers

et al. 2024

Preprint

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Mutations in the aristaless-related homeobox (ARX) gene are associated with a spectrum of neurodevelopmental disorders with neurologic phenotypes including epilepsy, intellectual disabilities and autism spectrum disorders, with or without structural malformations. Some features of these disorders have been linked to abnormal cortical interneuron (IN) development and function. Currently, more than 50 subtypes of cortical INs have been identified thanks to the single cell transcriptomics. The existence of these many IN subtypes, with differing functions, raise the likelihood that distinct phenotypic dysfunction be associated with specific IN subtype defects. Despite the functional significance of each IN subtype, the molecular mechanisms underlying their development remain incompletely understood. To further extend our understanding of IN subtype development and to evaluate the implications of subtype defects, different types of Arx mutation models were investigated: conditional loss of function mutations of Arx (Arx cKO) driven by three IN-specific Cre lines (Gad2Cre, Nkx2.1Cre, and SstCre) and a poly-alanine tract expansion mutation (Arx(GCG)7). Single cell as well as total transcriptomic analysis, along with ARX chromatin immunoprecipitation sequencing (ChIP-seq), reveal that ARX regulates transcription of cortical IN development- and migration-associated genes. Our data obtained in embryonic and perinatal stage indicate that the relatively early loss of ARX in the progenitor cells or immature INs leads to IN subtype changes and migration defects, whereas its loss in postmitotic INs did not. On the other hand, the poly-alanine tract expansion mutation results in IN migration defects without affecting IN subtype development during embryonic stages, although postnatal reduction of certain subtypes of INs were detected. Our data provide new insights into how different mutations in the same gene can result in a spectrum of clinical phenotypes.

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Origin, Development, and Synaptogenesis of Cortical Interneurons

Cited by 20 publications

References 217 publications

The impact of maternal immune activation on embryonic brain development

The impact of maternal immune activation on embryonic brain development

Astrocyte-Secreted Neurocan Controls Inhibitory Synapse Formation and Function

ARX regulates cortical interneuron differentiation and migration

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