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<p>Schizophrenia (SCZ) is a severe and hereditary neurodevelopmental disorder with unknown etiology. Here, we found that the SCZ risk gene <i>BRD2</i>, as an epigenetic reader, is consistently expressed in developing mouse and human cortical astrocytes. Astrocyte-specific <i>Brd2</i> knockout in mice leads to dysregulation of immune responses and reduces Fgf17 expression, resulting in SCZ-like behaviors, including impaired sensorimotor gating, memory, and cognitive deficits. Moreover, BRD2 inhibition using JQ1 in forebrain organoids leads to FGF17 reduction, inducing developmental deficits involved in neural patterning and gliogenesis. The decrease of FGF17 expression was also found in SCZ patient-derived forebrain organoids, similar to BRD2-inhibited forebrain organoids. FGF17 treatment partially rescued the disrupted gene expression in BRD2-inhibited human forebrain organoids. Taken together, these findings suggest that disrupting the BRD2-FGF17 signaling pathway in early brain development may contribute to the pathogenesis of schizophrenia and may represent a potential therapeutic target for SCZ.</p>

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Dysregulation of the BRD2-FGF17 Signal Pathway Induces Abnormal Forebrain Development Associated with Schizophrenia

  • 期刊论文

  • 发表日期：

    2025年9月14日

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  • Xiao Yu,
  • Jiacheng Du,
  • Chenger Zhou,
  • Yongheng Huang,
  • Huijuan Li,
  • Bruce M. Cohen,
  • Sangmi Chung,
  • Zhicheng Shao

摘要

Schizophrenia (SCZ) is a severe and hereditary neurodevelopmental disorder with unknown etiology. Here, we found that the SCZ risk gene BRD2, as an epigenetic reader, is consistently expressed in developing mouse and human cortical astrocytes. Astrocyte-specific Brd2 knockout in mice leads to dysregulation of immune responses and reduces Fgf17 expression, resulting in SCZ-like behaviors, including impaired sensorimotor gating, memory, and cognitive deficits. Moreover, BRD2 inhibition using JQ1 in forebrain organoids leads to FGF17 reduction, inducing developmental deficits involved in neural patterning and gliogenesis. The decrease of FGF17 expression was also found in SCZ patient-derived forebrain organoids, similar to BRD2-inhibited forebrain organoids. FGF17 treatment partially rescued the disrupted gene expression in BRD2-inhibited human forebrain organoids. Taken together, these findings suggest that disrupting the BRD2-FGF17 signaling pathway in early brain development may contribute to the pathogenesis of schizophrenia and may represent a potential therapeutic target for SCZ.