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

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.

Epileptic spasms related to neuronal differentiation factor 2 (NEUROD2) mutation respond to combined vigabatrin and high dose prednisolone therapy

“…Although cessation of clinical ES was achieved with a combination of vigabatrin and highdose prednisolone treatment, she had multiple relapses and global developmental delay. Our patient phenotype shared similar clinical onset of ES with a milder developmental delay than the previously reported two patients with a similar p. E130Q pathogenic variant [7,8] (Table 1).…”

“…Specifically, NEUROD2 regulates neuronal migration and differentiation and balances synaptic neurotransmission by promoting inhibitory synaptic drive and decreasing cell-intrinsic neuronal excitability [4,5]. Recently, NEU-ROD2 mutation has been shown to be the causative of neurodevelopmental disorders (NDDs) with core clinical features including intellectual disability, autism spectrum disorders, and speech disturbance [6][7][8]. However, there are limited data about the treatment course of ES with combined vigabatrin and high-dose prednisolone in the NEUROD2-related NDD syndrome.…”

Modelling Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) Using Mice and Zebrafish

“…Reversal learning deficits in the Morris water maze and increased susceptibility to pentylenetetrazol (PTZ)-induced seizures [170] Neuronal differentiation 2 (Neurod2) Social interaction deficits, stereotypies, hyperactivity, occasionally spontaneous seizures [171] Table 6. Cont.…”

Accounting for cis-regulatory constraint prioritizes genes likely to affect species-specific traits

“…Fig. 3A) (Platzer et al 2018; Paciorkowski et al 2013; Runge et al 2021). Differences in the expression of haploinsufficient genes are more likely to have phenotypic consequences than differences in the expression of genes for which loss of one copy has no clear phenotypic effect.…”