Synaptotagmin-11 deficiency in dopamine neurons in adolescence mediates schizophrenia-relevant behaviors
Yang Chen1Yu-hao Gu1Xiao-peng Li2Qian Song1An-qi Wei1Bian-bian Wang1Ze-xin Jing1Huadong Xu2Xinjiang Kang2Changhe Wang1
1. Center for Mitochondrial Biology and Medicine,The Key Laboratory of Biomedical Information Engineering of Ministry of Education,School of Life Science and Technology and Frontier Institute of Science and Technology,Xi'an Jiaotong University2. DOE-Key Lab of Medical Electrophysiology,Institute of Cardiovascular Research,Southwest Medical University
摘要：Schizophrenia,a severe devastating neuropsychiatric disease,affecting 1%population globally.And it’s a neurodevelopment disease.However,the mechanism underlying disturbance of maturational processes in schizophrenia remains unclear.Dopamine hypothesis is the most widely accepted pathological mechanism.But the negative symptoms are not sensitive to the Dopamine system targeted drugs.So the dopamine hypothesis is still debated.Synaptotagmin 11,a kind of Ca2+ non-binding Synaptotagmin,is a newly-found susceptibility gene of schizophrenia.Here,we probed the hypothesis that social defect of schizophrenia originates from hyperactivity of midbrain pathway during the critical neurodevelopment stage.We prepared the DAspecific conditional knockout Syt 11 mice,and observed apparent SCZ-like social deficit.Moreover,we impressively found that only specific syt11 knockout in DA neuron before juvenile but not adult generate the social deficit.Correspondingly,the phenomenon was further verified by optogenetic and chemical geneticsmanipulation ofVTA DA neurons during different period.And the social defect can be rescued by the D2 antagonist or agonist in the specific brain area during the juvenile stage.Mechanistically,we discovered that syt11 loss induced the hyperactivity of DA neurons.Taken together,our study demonstrated a novel theory that the hyeractivity of DA neurons during neurodevelopment period will lead to schizophrenia-like behavior,underlying the pathogenethesis of syt11 associated schizophrenia.