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Disruption of NEUROD2 causes a neurodevelopmental syndrome with autistic features via cell-autonomous defects in forebrain glutamatergic neurons

Karen Runge 1 Rémi Mathieu 1 Stéphane Bugeon 2 Sahra Lafi 1, 2 Corinne Beurrier 2 Surajit Sahu 1 Fabienne Schaller 1 Arthur Loubat 1 Leonard Herault 3 Stéphane Gaillard 4 Emilie Pallesi-Pocachard 1 Aurélie Montheil 1 Andreas Bosio 5 Jill Rosenfeld 6 Eva Hudson 7 Kristin Lindstrom 8 Saadet Mercimek-Andrews 9 Lauren Jeffries 10 Arie van Haeringen 11 Olivier Vanakker 12 Audrey van Hecke 13, 14 Dina Amrom 13, 14, 15 Sebastien Küry 16, 17 Chana Ratner 18 Reena Jethva 18 Candace Gamble 7 Bernard Jacq 2 Laurent Fasano 2 Gabriel Santpere 10 Belen Lorente-Galdos 10 Nenad Sestan 10 Antoinette Gelot 1, 19 Sylvie Giacuzz 19 Sandra Goebbels 20 Alfonso Represa 1 Carlos Cardoso 1 Harold Cremer 2 Antoine de Chevigny 1 
Abstract : 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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Submitted on : Wednesday, September 15, 2021 - 9:00:40 AM
Last modification on : Friday, August 5, 2022 - 3:36:13 AM


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Karen Runge, Rémi Mathieu, Stéphane Bugeon, Sahra Lafi, Corinne Beurrier, et al.. Disruption of NEUROD2 causes a neurodevelopmental syndrome with autistic features via cell-autonomous defects in forebrain glutamatergic neurons. Molecular Psychiatry, Nature Publishing Group, 2021, ⟨10.1038/s41380-021-01179-x⟩. ⟨hal-03328734⟩



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