Pengfei Jiang1  · Mingzhao Su3  · Xue Zhou1  · Baoshen Zhang1  · Jie Sun2  · Ru Ba1  · Junhua Liu1  · 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 and Key Laboratory of Clinical Science and Research, Zhongda Hospital, Southeast University, Nanjing 210009, China 

3 Central Laboratory, Linyi People’s Hospital, Linyi 276000, China

Abstract

Schizophrenia (SCZ) is characterized by heterogeneous symptoms including abnormal perception, social withdrawal, and cognitive deficits. Parvalbumin-positive (PV⁺) interneurons are particularly vulnerable in SCZ; however, the underlying cellular basis remains unclear. In this study, we found that selective deletion of the SCZ risk gene Foxg1 in PV⁺ interneurons of mice recapitulated aspects of the disease phenotype, including impaired sensorimotor gating, anxiety-like behavior, social deficits, and cognitive impairments. Foxg1 deficiency caused dendritic simplification, reduced spine density, and impaired synaptic transmission in PV⁺ interneurons of the prelimbic cortex. Our findings indicate that FOXG1 directly drives a set of SCZ risk genes that encode synaptic receptors, adhesion molecules, scaffolding proteins, transporters, ion channels, and vesicle-trafficking proteins, thereby orchestrating PV⁺ interneuron synaptic function. Notably, FOXG1 activates the transcription of metabotropic glutamate receptor 3 (mGluR3), and pharmacological potentiation of mGluR3 activity alleviates behavioral deficits in Foxg1 conditional knockout mice. In conclusion, our findings identify a novel role for Foxg1 in PV⁺ interneurons, providing new mechanistic insights into their vulnerability to SCZ.

Keywords

Schizophrenia; Parvalbumin⁺ interneurons; Dendritic development; Synaptic transmission; Sensorimotor gating; Anxiety; Social behavior; Cognition

[Springerlink]