Genetic Disruption of Cortical Interneuron Development Causes Region- and GABA Cell Type-Specific Deficits, Epilepsy, and Behavioral Dysfunction

Abstract The multiplex role of cadherin-based adhesion complexes during development of pallial excitatory neurons has been thoroughly characterized. In contrast, much less is known about their function during interneuron development. Here, we report that conditional removal of N-cadherin (Cdh2) from postmitotic neuroblasts of the subpallium results in a decreased number of Gad65-GFP-positive interneurons in the adult cortex. We also found that interneuron precursor migration into the pallium was already delayed at E14. Using immunohistochemistry and TUNEL assay in the embryonic subpallium, we excluded decreased mitosis and elevated cell death as possible sources of this defect. Moreover, by analyzing the interneuron composition of the adult somatosensory cortex, we uncovered an unexpected interneuron-type-specific defect caused by Cdh2-loss. This was not due to a fate-switch between interneuron populations or altered target selection during migration. Instead, potentially due to the migration delay, part of the precursors failed to enter the cortical plate and consequently got eliminated at early postnatal stages. In summary, our results indicate that Cdh2-mediated interactions are necessary for migration and survival during the postmitotic phase of interneuron development. Furthermore, we also propose that unlike in pallial glutamatergic cells, Cdh2 is not universal, rather a cell type-specific factor during this process.

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PlexinA4-Semaphorin3A mediated crosstalk between main cortical interneuron classes is required for superficial interneurons lamination

10.1101/2020.06.23.166926 ◽

2020 ◽

Author(s):

Greta Limoni ◽

Mathieu Niquille ◽

Sahana Murthy ◽

Denis Jabaudon ◽

Alexandre Dayer

Keyword(s):

Cerebral Cortex ◽

Serotonin Receptor ◽

Deep Layer ◽

Cortical Plate ◽

Inhibitory Interneurons ◽

Cell Type ◽

Cortical Layers ◽

Cortical Interneuron ◽

Cell Type Specific ◽

Genetic Deletion

SummaryIn the mammalian cerebral cortex, the developmental events governing the allocation of different classes of inhibitory interneurons (INs) into distinct cortical layers are poorly understood. Here we report that the guidance receptor PlexinA4 (PLXNA4) is upregulated in serotonin receptor 3a-expressing (HTR3A+) cortical INs (hINs) as they invade the cortical plate and that it regulates their laminar allocation to superficial cortical layers. We find that the PLXNA4 ligand Semaphorin3A (SEMA3A) acts as a chemorepulsive factor on hINs migrating into the nascent cortex and demonstrate that SEMA3A specifically controls their laminar positioning through PLXNA4. We identify that deep layer INs constitute a major source of SEMA3A in the developing cortex and demonstrate that cell-type specific genetic deletion of SEMA3A in these INs specifically affects the laminar allocation of hINs. These data demonstrate that in the neocortex, deep layer INs control the laminar allocation of hINs into superficial layers.

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The organization and developmental establishment of cortical interneuron presynaptic circuits

10.1101/2020.09.17.302117 ◽

2020 ◽

Author(s):

Gabrielle Pouchelon ◽

Yannick Bollmann ◽

Elaine Fisher ◽

Chimuanya K Agba ◽

Qing Xu ◽

...

Keyword(s):

Fragile X ◽

Inhibitory Interneurons ◽

Loss Of Function ◽

Cortical Circuits ◽

Cell Type ◽

Cortical Interneuron ◽

First Order ◽

Cortical Areas ◽

Cell Type Specific ◽

Do So

Sensory and cognitive functions are processed in discrete cortical areas and depend upon the integration of long range cortical and subcortical inputs. PV and SST inhibitory interneurons (cINs) gate these inputs and failure to do so properly is implicated in many neurodevelopmental disorders. The logic by which these interneuron populations are integrated into cortical circuits and how these vary across sensory versus associative cortical areas is unknown. To answer this question, we began by surveying the breadth of afferents impinging upon PV and SST cINs within distinct cortical areas. We found that presynaptic inputs to both cIN populations are similar and primarily dictated by their areal location. By contrast, the timing of when they receive these afferents is cell-type specific. In sensory regions, both SST and PV cINs initially receive thalamocortical first order inputs. While by adulthood PV cINs remain heavily skewed towards first order inputs, SST cINs receive an equal balance of first and higher order thalamic afferents. Remarkably, while perturbations to sensory experience affect PV cIN thalamocortical connectivity, SST cIN connectivity is disrupted in a model of fragile X syndrome (Fmr1 loss of function) but not a model of ASD (Shank3B loss of function). Altogether, these data provide a comprehensive map of cIN afferents within different functional cortical areas and reveal the region-specific logic by which PV and SST cIN circuits are established.

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Rbfox1 mediates cell-type-specific splicing in cortical interneurons

10.1101/305904 ◽

2018 ◽

Author(s):

Xavier Hubert Jaglin ◽

Brie Wamsley ◽

Emilia Favuzzi ◽

Giulia Quattracolo ◽

Maximiliano José Nigro ◽

...

Keyword(s):

Alternative Splicing ◽

Cell Type ◽

Cortical Interneuron ◽

Physiological Properties ◽

Cortical Interneurons ◽

Molecular Determinants ◽

Splicing Regulator ◽

Cell Type Specific ◽

And Function ◽

Activity Dependent

SummaryCortical interneurons display a remarkable diversity in their morphology, physiological properties and connectivity. Elucidating the molecular determinants underlying this heterogeneity is essential for understanding interneuron development and function. We discovered that alternative splicing differentially regulates the integration of somatostatin- and parvalbumin-expressing interneurons into nascent cortical circuits through the cell-type specific tailoring of mRNAs. Specifically, we identified a role for the activity-dependent splicing regulator Rbfox1 in the development of cortical interneuron subtype specific efferent connectivity. Our work demonstrates that Rbfox1 mediates largely non-overlapping alternative splicing programs within two distinct but related classes of interneurons.

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