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<p>Schizophrenia (SCZ) is characterized by heterogeneous symptoms including abnormal perception, social withdrawal, and cognitive deficits. Parvalbumin-positive (PV<sup>+</sup>) interneurons are particularly vulnerable in SCZ; however, the underlying cellular basis remains unclear. In this study, we found that selective deletion of&#xa0;the SCZ risk gene <i>Foxg1</i> in PV<sup>+</sup> interneurons of mice recapitulated aspects of the disease phenotype, including impaired sensorimotor gating, anxiety-like behavior, social deficits, and cognitive impairments. <i>Foxg1</i> deficiency caused dendritic simplification, reduced spine density, and impaired synaptic transmission in PV<sup>+</sup> 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<sup>+</sup> interneuron synaptic function. Notably, FOXG1 activates the transcription of metabotropic glutamate receptor 3 (mGluR3), and pharmacological potentiation of mGluR3 activity alleviates behavioral deficits in <i>Foxg1</i> conditional knockout mice. In conclusion, our findings identify a novel role for <i>Foxg1</i> in PV<sup>+</sup> interneurons, providing new mechanistic insights into their vulnerability to SCZ.</p>

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FOXG1 Transcriptionally Orchestrates Parvalbumin+ Interneuron Function Contributing to Schizophrenia Pathology

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月23日

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  • Pengfei Jiang,
  • Mingzhao Su,
  • Xue Zhou,
  • Baoshen Zhang,
  • Jie Sun,
  • Ru Ba,
  • Junhua Liu,
  • Chunjie Zhao

摘要

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.