期刊
MOLECULAR PSYCHIATRY
卷 26, 期 11, 页码 6125-6148出版社
SPRINGERNATURE
DOI: 10.1038/s41380-021-01179-x
关键词
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资金
- Agence Nationale de la Recherche [ANR-13-JSV4-0006, ANR-13-BSV4-0013-01]
- Fondation Pour la Recherche sur le Cerveau
- Fondation Lejeune
- European Community
- Fritz Thyssen Foundation [10.15.2.022MN]
- European Network on Brain Malformations (NeuroMIG) [CA16118]
- la Caixa Foundation [100010434]
- Ministerio de Ciencia e Innovacion, Spain [PID2019-104700GA-I00]
- Inserm
- GIS IBiSA
- Aix-Marseille Universite
- Fondation Pour la Recherche Medicale
- [LCF/BQ/PI19/11690010]
- [ANR-10-INBS-0009-10]
- Agence Nationale de la Recherche (ANR) [ANR-13-BSV4-0013, ANR-13-JSV4-0006] Funding Source: Agence Nationale de la Recherche (ANR)
The transcription factor NEUROD2 plays a crucial role in cortical development, with its knockout leading to over-migration of cortical projection neurons, dysregulation of spine density and turnover, and increased intrinsic excitability. Dysfunctional NEUROD2 is also associated with neurodevelopmental disorders including autism spectrum disorders.
While the transcription factor NEUROD2 has recently been associated with epilepsy, its precise role during nervous system development remains unclear. Using a multi-scale approach, we set out to understand how Neurod2 deletion affects the development of the cerebral cortex in mice. In Neurod2 KO embryos, cortical projection neurons over-migrated, thereby altering the final size and position of layers. In juvenile and adults, spine density and turnover were dysregulated in apical but not basal compartments in layer 5 neurons. Patch-clamp recordings in layer 5 neurons of juvenile mice revealed increased intrinsic excitability. Bulk RNA sequencing showed dysregulated expression of many genes associated with neuronal excitability and synaptic function, whose human orthologs were strongly associated with autism spectrum disorders (ASD). At the behavior level, Neurod2 KO mice displayed social interaction deficits, stereotypies, hyperactivity, and occasionally spontaneous seizures. Mice heterozygous for Neurod2 had similar defects, indicating that Neurod2 is haploinsufficient. Finally, specific deletion of Neurod2 in forebrain excitatory neurons recapitulated cellular and behavioral phenotypes found in constitutive KO mice, revealing the region-specific contribution of dysfunctional Neurod2 in symptoms. Informed by these neurobehavioral features in mouse mutants, we identified eleven patients from eight families with a neurodevelopmental disorder including intellectual disability and ASD associated with NEUROD2 pathogenic mutations. Our findings demonstrate crucial roles for Neurod2 in neocortical development, whose alterations can cause neurodevelopmental disorders including intellectual disability and ASD.
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