Baoshen Zhang1  · Daxiang Xu1  · Shuangshuang Dong1  · Pei Zhu1  · Pengfei Jiang1  · Jie Sun2  · Junhua Liu1  · Huanxin Chen3  · Chunjie Zhao1,2

1 Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, School of Medicine, Southeast University, Nanjing 210009, China 

2 Department of Anesthesiology, Surgery and Pain Management & Key Laboratory of Clinical Science and Research, Zhongda Hospital, Nanjing 210009, China 

3 Huzhou Third Municipal Hospital, The Affiliated Hospital of Huzhou University, Huzhou 313000, China

Abstract

Autism spectrum disorder (ASD) pathophysiology often involves striatal dysfunction, yet the underlying mechanisms remain unclear. Mutations in Forkhead box G1 (FOXG1) cause FOXG1 syndrome, a condition sharing core ASD features. Here, loss of Foxg1 in the indirect pathway spiny projection neurons (iSPNs) in mice recapitulates ASD symptoms, including social, language, and fine movement deficits. Foxg1 deficiency causes dendritic simplification, spine reduction, and impairs excitatory synaptic transmission. Transcriptome reveals that FOXG1 drives gene networks to multidimensionally control synaptic functions from spine morphogenesis, synaptic maturation, ion transmembrane transport, glutamate receptor clustering, to neurotransmitter release and synaptic transmission. Importantly, FOXG1 directly activates the transcription of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunits, and pharmacological potentiation of AMPAR activity normalizes synaptic function and rescues behavioral deficits. Our study provides a new perspective on the relationship between FOXG1 and ASD etiology in iSPNs and suggests the potential of AMPAR activation as a therapeutic intervention for ASD and FOXG1 Syndrome.

Keywords

Autism spectrum disorder; Striatum; Indirect pathway spiny projection neurons;· AMPAR; Synaptogenesis; Synaptic transmission; Dendritic development; Forkhead box G1

[SpringerLink]