Disruption of NEUROD2 causes a neurodevelopmental syndrome with autistic features via cell-autonomous defects in forebrain glutamatergic neurons - Aix-Marseille Université Access content directly
Journal Articles Molecular Psychiatry Year : 2021

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

Karen Runge
  • Function : Author
Rémi Mathieu
  • Function : Author
Stéphane Bugeon
  • Function : Author
Sahra Lafi
  • Function : Author
Surajit Sahu
  • Function : Author
Fabienne Schaller
  • Function : Author
Arthur Loubat
  • Function : Author
Leonard Herault
  • Function : Author
Stéphane Gaillard
  • Function : Author
Emilie Pallesi-Pocachard
  • Function : Author
Aurélie Montheil
  • Function : Author
Andreas Bosio
  • Function : Author
Jill A Rosenfeld
Eva Hudson
  • Function : Author
Kristin Lindstrom
  • Function : Author
Saadet Mercimek-Andrews
  • Function : Author
Lauren Jeffries
  • Function : Author
Arie van Haeringen
  • Function : Author
Olivier Vanakker
  • Function : Author
Audrey van Hecke
  • Function : Author
Dina Amrom
  • Function : Author
Sebastien Küry
  • Function : Author
Chana Ratner
  • Function : Author
Reena Jethva
  • Function : Author
Candace Gamble
  • Function : Author
Bernard Jacq
  • Function : Author
Laurent Fasano
Gabriel Santpere
Belen Lorente-Galdos
  • Function : Author
Nenad Sestan
Antoinette Gelot
  • Function : Author
Sylvie Giacuzz
  • Function : Author
Sandra Goebbels
  • Function : Author
Alfonso Represa
  • Function : Author
Carlos Cardoso
Harold Cremer
  • Function : Author
Antoine de Chevigny

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 regionspecific 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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Neurobiology
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Dates and versions

hal-03424186 , version 1 (10-11-2021)

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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, 2021, ⟨10.1038/s41380-021-01179-x⟩. ⟨hal-03424186⟩
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