Synaptic Functions of Disrupted-in-Schizophrenia-1 (DISC1)

描述（由申请人提供）：精神分裂症1型（DISC 1）是精神分裂症和相关精神疾病的遗传风险因素，然而DISC 1在成熟神经元中的突触功能在很大程度上是未知的。新的证据表明，突触传递的改变可能是精神分裂症的核心特征和基本病理，因此本项目的目标是了解DISC 1在调节前额叶皮层（PFC）神经元突触蛋白功能中的作用。我们假设DISC 1通过调节NMDAR和GABAAR通道对突触传递和可塑性产生重要影响，这两个关键靶点参与认知和情感过程，并且DISC 1的突触功能在精神分裂症中改变。两个具体的目标将被解决，研究DISC 1的表达，贩运和功能的NMDAR和GABAAR在大鼠PFC神经元的影响，使用在体外和体内敲低DISC 1或过表达的全长或C-末端截短DISC 1。DISC 1调节NMDAR和GABAAR的潜在机制也将被探索。我们的研究结果不仅揭示了DISC 1突触功能的重要机制，而且还可能为治疗精神障碍的更有效治疗策略提供新的靶点。

DESCRIPTION (provided by applicant): Disrupted-in-Schizophrenia 1 (DISC1) is a genetic risk factor for schizophrenia and related mental illnesses, however the synaptic functions of DISC1 in mature neurons are largely unknown. Emerging evidence suggests that alterations of synaptic transmission might be the core feature and fundamental pathology of schizophrenia, thus the goal of this project is to understand the role of DISC1 in regulating synaptic protein functions in prefrontal cortical (PFC) neurons. We hypothesize that DISC1 exerts an important impact on synaptic transmission and plasticity by regulating NMDAR and GABAAR channels, two key targets involved in cognitive and emotional processes, and the synaptic function of DISC1 is altered in schizophrenia. Two specific aims will be addressed to examine the impact of DISC1 on the expression, trafficking and function of NMDARs and GABAARs in rat PFC neurons, using in vitro and in vivo knockdown of DISC1 or overexpression of full-length or C-terminal truncated DISC1. The potential mechanisms for DISC1 regulation of NMDARs and GABAARs will also be explored. Our results would not only reveal significant mechanistic insights into the synaptic functions of DISC1, but may also provide novel targets for more effective therapeutic strategies to treat mental disorders.