Xiao Yu1  · Jiacheng Du1  · Chenger Zhou1  · Yongheng Huang1,2 · Huijuan Li1  · Bruce M. Cohen3  · Sangmi Chung4  · Zhicheng Shao1

1 Department of Neurology, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Zhongshan Hospital, Institute for Translational Brain Research, Fudan University, Shanghai 200032, China 

2 Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Xiamen University, Xiamen 361005, China 

3 Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA 

4 Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY 10595, USA

Abstract

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.

Keywords

Brain organoid; Schizophrenia; BRD2; FGF17; Forebrain development

[SpringerLink]