Imbalance of Excitatory/Inhibitory Neuron Differentiation in Neurodevelopmental Disorders with an NR2F1 Point Mutation

Abstract

Summary: Recent studies have revealed an essential role for embryonic cortical development in the pathophysiology of neurodevelopmental disorders, including autism spectrum disorder (ASD). However, the genetic basis and underlying mechanisms remain unclear. Here, we generate mutant human embryonic stem cell lines (Mut hESCs) carrying an NR2F1-R112K mutation that has been identified in a patient with ASD features and investigate their neurodevelopmental alterations. Mut hESCs overproduce ventral telencephalic neuron progenitors (ventral NPCs) and underproduce dorsal NPCs, causing the imbalance of excitatory/inhibitory neurons. These alterations can be mainly attributed to the aberrantly activated Hedgehog signaling pathway. Moreover, the corresponding Nr2f1 point-mutant mice display a similar excitatory/inhibitory neuron imbalance and abnormal behaviors. Antagonizing the increased inhibitory synaptic transmission partially alleviates their behavioral deficits. Together, our results suggest that the NR2F1-dependent imbalance of excitatory/inhibitory neuron differentiation caused by the activated Hedgehog pathway is one precursor of neurodevelopmental disorders and may enlighten the therapeutic approaches. : Zhang et al. find that a NR2F1-R112K mutation promotes inhibitory neuron differentiation by activating the Hedgehog signaling pathway, and corresponding mutant mice display behavioral deficits related to neurodevelopmental disorders, including autistic spectrum disorder (ASD), which could be partially alleviated by antagonizing the inhibitory synaptic transmission. Keywords: neurodevelopmental disorders, autism spectrum disorders, excitatory neuron, inhibitory neuron, dorsal neuron progenitor cell, ventral neuron progenitor cell, E/I imbalance, Hedgehog signaling pathway, NR2F1