Pathological oligodendrocyte precursor cells revealed in human schizophrenic brains and trigger schizophrenia-like behaviors and synaptic defects in genetic animal model

作者全名："Yu, Guangdan; Su, Yixun; Guo, Chen; Yi, Chenju; Yu, Bin; Chen, Hui; Cui, Yihui; Wang, Xiaorui; Wang, Yuxin; Chen, Xiaoying; Wang, Shouyu; Wang, Qi; Chen, Xianjun; Hu, Xuelian; Mei, Feng; Verkhratsky, Alexei; Xiao, Lan; Niu, Jianqin"

作者地址："[Yu, Guangdan; Su, Yixun; Yu, Bin; Wang, Xiaorui; Wang, Yuxin; Chen, Xiaoying; Wang, Shouyu; Wang, Qi; Hu, Xuelian; Mei, Feng; Xiao, Lan; Niu, Jianqin] Third Mil Med Univ, Brain & Intelligence Res Key Lab, Chongqing Key Lab Neurobiol, Chongqing Educ Commiss,Dept Histol & Embryol, Chongqing, Peoples R China; [Su, Yixun; Yi, Chenju; Wang, Qi] Sun Yat Sen Univ, Res Ctr, Affiliated Hosp 7, Shenzhen, Peoples R China; [Guo, Chen; Cui, Yihui] Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Neurobiol, Sch Med, Hangzhou, Peoples R China; [Guo, Chen; Cui, Yihui] Zhejiang Univ, Sir Run Run Shaw Hosp, Dept Neurol, Sch Med, Hangzhou, Peoples R China; [Yu, Bin; Xiao, Lan] Third Mil Med Univ, Dept Neurosurg, Affiliated Hosp 2, Chongqing, Peoples R China; [Chen, Hui] Univ Technol Sydney, Fac Sci, Sch Life Sci, Sydney, NSW, Australia; [Chen, Xianjun] Chongqing Med Univ, Coll Basic Med Sci, Dept Physiol, Chongqing, Peoples R China; [Verkhratsky, Alexei] Univ Manchester, Fac Biol Med & Hlth, Manchester, Lancs, England; [Verkhratsky, Alexei] Ikerbasque, Achucarro Ctr Neurosci, Bilbao 48011, Spain"

通信作者："Xiao, L; Niu, JQ (通讯作者)，Third Mil Med Univ, Brain & Intelligence Res Key Lab, Chongqing Key Lab Neurobiol, Chongqing Educ Commiss,Dept Histol & Embryol, Chongqing, Peoples R China.; Xiao, L (通讯作者)，Third Mil Med Univ, Dept Neurosurg, Affiliated Hosp 2, Chongqing, Peoples R China.; Verkhratsky, A (通讯作者)，Univ Manchester, Fac Biol Med & Hlth, Manchester, Lancs, England.; Verkhratsky, A (通讯作者)，Ikerbasque, Achucarro Ctr Neurosci, Bilbao 48011, Spain."

来源：MOLECULAR PSYCHIATRY

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:000860141900001

JCR分区：Q1

影响因子：11

年份：2022

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：　

摘要："Although the link of white matter to pathophysiology of schizophrenia is documented, loss of myelin is not detected in patients at the early stages of the disease, suggesting that pathological evolution of schizophrenia may occur before significant myelin loss. Disrupted-in-schizophrenia-1 (DISC1) protein is highly expressed in oligodendrocyte precursor cells (OPCs) and regulates their maturation. Recently, DISC1-Delta 3, a major DISC1 variant that lacks exon 3, has been identified in schizophrenia patients, although its pathological significance remains unknown. In this study, we detected in schizophrenia patients a previously unidentified pathological phenotype of OPCs exhibiting excessive branching. We replicated this phenotype by generating a mouse strain expressing DISC1-Delta 3 gene in OPCs. We further demonstrated that pathological OPCs, rather than myelin defects, drive the onset of schizophrenic phenotype by hyperactivating OPCs' Wnt/beta-catenin pathway, which consequently upregulates Wnt Inhibitory Factor 1 (Wif1), leading to the aberrant synaptic formation and neuronal activity. Suppressing Wif1 in OPCs rescues synaptic loss and behavioral disorders in DISC1-Delta 3 mice. Our findings reveal the pathogenetic role of OPC-specific DISC1-Delta 3 variant in the onset of schizophrenia and highlight the therapeutic potential of Wif1 as an alternative target for the treatment of this disease."

基金机构："National Key Research and Development Program of China [2021ZD0201703]; National Nature Science Foundation of China (NSFC) [32070964, 31871045, 31970921, 31921003, 81971309, 32170980]; Guangdong Basic and Applied Basic Research Foundation [2019A1515011333]; Shenzhen Fundamental Research Program [JCYJ20190809161405495, JCYJ20210324123212035, RCYX20200714114644167]; Zhejiang Provincial Natural Science Foundation of China [LR19C090001]"

基金资助正文："National Key Research and Development Program of China (2021ZD0201703 to JN and LX). National Nature Science Foundation of China (NSFC 32070964 and 31871045 to JN; 31970921 and 31921003 to LX; 81971309 and 32170980 to CY). Guangdong Basic and Applied Basic Research Foundation (2019A1515011333 to CY). Shenzhen Fundamental Research Program (JCYJ20190809161405495, JCYJ20210324123212035, and RCYX20200714114644167 to CY). Zhejiang Provincial Natural Science Foundation of China (LR19C090001 to YC)."