FOXG1 Transcriptionally Orchestrates Parvalbumin+ Interneuron Function Contributing to Schizophrenia Pathology.
TL;DR
A novel role for Foxg1 is identified in PV+ interneurons, providing new mechanistic insights into their vulnerability to SCZ, and pharmacological potentiation of mGluR3 activity alleviates behavioral deficits in Foxg1 conditional knockout mice.
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.