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

描述（由申请人提供）：精神分裂症1号蛋白紊乱（DISC1）是精神分裂症和相关精神疾病的遗传危险因素，然而，成熟神经元中DISC1的突触功能在很大程度上是未知的。越来越多的证据表明，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DISC1在调节前额叶皮质（PFC）神经元突触蛋白功能中的作用。我们假设DISC1通过调节NMDAR和GABAAR通道（两个参与认知和情绪过程的关键靶点）对突触传递和可塑性产生重要影响，并且在精神分裂症中DISC1的突触功能发生改变。通过体外和体内敲低DISC1或过表达全长或c端截断DISC1，研究DISC1对大鼠PFC神经元中NMDARs和GABAARs的表达、运输和功能的影响。DISC1调控NMDARs和GABAARs的潜在机制也将被探讨。我们的研究结果不仅揭示了DISC1突触功能的重要机制，而且可能为治疗精神障碍提供更有效的治疗策略。

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.