Molecular, synaptic and circuit basis for 14-3-3 dysfunction-induced behavioral deficits

项目摘要/摘要： 对突触发育和连接的精确控制对正常的大脑功能至关重要。中的缺陷 突触传递导致神经元回路中断，这是各种疾病的根本原因 神经精神疾病。为了了解关键突触调节蛋白在体内的功能，我们有 对一种新的小鼠模型14-3-3进行了研究，14-3-3是一个富含大脑的蛋白质家族，与 突触功能和精神分裂症的基因联系。我们发现，抑制14-3-3的功能在 小鼠大脑损害突触传递，并导致与 已建立的精神分裂症小鼠模型的核心内表型。我们进一步鉴定了NMDA受体是 14-3-3信号在前脑神经元兴奋性突触的潜在靶点之一。 这些发现令人兴奋，并表明14-3-3功能障碍的小鼠模型可能提供了独特的工具 阐明精神分裂症相关行为发展的突触机制。在这 提议，我们将开发更精确的动物模型来定义大脑的区域和发育- 14-3-3功能障碍对行为缺陷的具体贡献；2)确定14-3-3功能障碍的影响 小鼠神经元兴奋性、突触生理和同步网络活动功能障碍 以及3)描述了14-3-3依赖调控的细胞和分子机制。 突触NMDA受体。 这项研究包含了我们三个实验室的专业知识、实力和现有资源。结果来自 这项研究将极大地促进我们对14-3-3蛋白及其蛋白的突触功能的理解 在精神障碍中的作用。

Project Summary/Abstract: Precise control of synaptic development and connectivity is essential for normal brain functions. Defects in synaptic transmissions lead to the disruption of neuronal circuits, which are the underlying cause of various neuropsychiatric diseases. To understand the in vivo functions of key synaptic regulatory proteins, we have conducted studies on a new mouse model for 14-3-3, which is a family of brain-rich proteins implicated in synaptic functions and genetically linked to schizophrenia. We found that inhibition of 14-3-3 functions in the mouse brain impairs synaptic transmission, and causes a variety of behavioral deficits that correspond to the core endophenotypes of established schizophrenia mouse models. We further identified the NMDA receptor as one of the potential targets of 14-3-3 signaling at excitatory synapses in forebrain neurons. These findings are exciting and suggest that mouse models of 14-3-3 dysfunction may provide unique tools to elucidate synaptic mechanisms underlying the development of schizophrenia-associated behaviors. In this proposal, we will 1) develop more precise animal models to define the brain regional- and developmental- specific contributions of 14-3-3 dysfunctions to behavioral deficits; 2) determine the impact of 14-3-3 dysfunctions on neuronal excitability, synaptic physiology and synchronized network activity in the mouse brain; and 3) delineate the cellular and molecular mechanisms underlying 14-3-3-dependent regulation of synaptic NMDA receptors. This research encompasses expertise, strength and existing resources in our three laboratories. Results from this study will significantly advance our understanding on the synaptic functions of 14-3-3 proteins and their role in mental disorders.