Disruption of FOXG1 Impairs the Development of Striatal dSPNs, Thereby Contributing to ASD-Like Phenotypes

Striatal dysfunction is a feature of autism spectrum disorder (ASD); however, the molecular mechanisms underlying its development remain unclear. Mutations in the transcription factor FOXG1 lead to FOXG1 syndrome, which shares core clinical features with ASD. In the present study, we conditionally deleted Foxg1 in the striatal direct pathway spiny projection neurons (dSPNs) to create Foxg1 conditional knockout (cKO) mice, which we found recapitulated classic ASD-like symptoms, including social deficits, communication impairments, and restricted repetitive behaviors. Loss of FOXG1 further resulted in simplified dendritic arborization and reduced dendritic spine density. We found that FOXG1 drives a set of ASD risk genes, including synaptic receptors and scaffolding proteins, to coordinate the development and function of dSPNs. Further, FOXG1 directly regulated the transcription of GABA B receptor subunit 2 to control the activity of dSPNs. Pharmacological enhancement of the GABA B receptor activity effectively restored the excitation/inhibition balance and ameliorated behavioral abnormalities in Foxg1 cKO mice. Our findings reveal a novel role for FOXG1 in dSPNs, provide new insights into the pathogenesis of ASD and FOXG1 syndrome, and indicate that targeting GABA B receptor activation may serve as a potential therapeutic strategy for ASD.