前额叶皮质PV神经元在少突胶质细胞缺失TET1致精神分裂症样行为中的作用机制研究

精神分裂症SCZ是一类严重的慢性神经系统功能紊乱疾病，虽然近年来少突胶质细胞OL功能异常被认为是SCZ发病的重要因素，但机制不清。申请人前期观察到在OL中条件性敲除DNA氧合酶TET1(Tet1cKO)将导致小鼠大脑髓鞘发育滞后，并出现SCZ样的行为学表型；同时Tet1cKO小鼠前额叶皮质PV中间神经元发育组成改变，神经元放电频率降低。因此我们推测Tet1cKO小鼠功能低下的PV神经元可能对周围锥体神经元的抑制作用减弱，并打破神经微环路的兴奋/抑制平衡，最终引起神经功能异常。在本项目中，我们将利用Tet1cKO小鼠，从神经元功能改变和OL基因表达谱的筛选结果入手，借助神经形态学、病毒标记、电生理、钙成像、光遗传、行为学等技术手段，探讨OL表观遗传修饰如何通过改变PV神经元的功能引起精神分裂症发病的详细机理。该研究将为我们从OL与神经元互作的角度揭示相关疾病的发生发展提供重要的实验依据。

Multiple lines of evidence in schizophrenia have implicated oligodendrocyte and myelin dysfunction in this disease, but the mechanism remains elusive. We have identified TET1 (Tet Methylcytosine Dioxygenase 1) and 5-hydroxymethylcytosine as novel epigenetic regulators for oligodendrocyte differentiation and conditional knockout Tet1 in oligodendrocytes (Tet1 cKO) impairs myelination, causes schizophrenia relevant behaviors. Meanwhile, the developmental plasticity and firing frequency of parvalbumin (PV) interneurons from prefrontal cortex is decreased in Tet1 cKO mice. Therefore, we speculate that oligodendrocyte dysfunction induced by TET1-5hmC depletion may cause malfunction in PV neurons, break excitation/inhibition balance of neural microcircuit and result in psychiatric disorders. Based on previous phenotypic observations and transcriptome data from Tet1 cKO mice, in current study we will apply histology, electrophysiology, Ca2+ imaging, optogenetics，behavior tests, et.al, identify the functional characteristics of PV interneurons in Tet1 cKO mice and investigate the crosstalk mechanism between oligodendrocyte and PV neurons in schizophrenia. These studies will greatly enrich our knowledge for the contributions of oligodendrocyte in regulating neural function as well as in psychiatric disorder pathogenesis.