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

14-3-3 功能障碍引起的行为缺陷的分子、突触和回路基础

基本信息

批准号：
10212908
负责人：
YI ZHOU
金额：
$ 37.88万
依托单位：
FLORIDA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-18 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10212908
关键词：
Address Affect Animal Model Attenuated Behavior Behavioral Brain Cell physiology Cells Complex Defect Development Electrophysiology (science)Equilibrium Excitatory Synapse Exhibits Family Functional disorder Hippocampus (Brain)Homologous Protein Impairment Injections Knock-out Knockout Mice Knowledge Laboratories Lead Link Mediating Mental disorders Molecular Mus N-Methyl-D-Aspartate Receptors Neurobiology Neurons Pathogenicity Physiology Play Prefrontal Cortex Property Prosencephalon Protein Isoforms Proteins Pyramidal Cells Regulation Reporting Research Resources Role Schizophrenia Signal Transduction Signaling Protein Surface Symptoms Synapses Synaptic Transmission Testing Transgenes Transgenic Model Wild Type Mouse conditional knockout endophenotype excitatory neuron genetic regulatory protein hippocampal pyramidal neuron human disease in vivo information processing inhibitor/antagonist mouse model neural circuit neural network neuronal circuit disruption neuronal excitability neuropsychiatric disorder novel therapeutic intervention protein complex small hairpin RNA synaptic function therapeutically effective tool transgene expression

项目摘要

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.

项目概要/摘要：精确控制突触发育和连接对于正常的大脑功能至关重要。缺陷突触传递导致神经元回路的中断，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的体内功能，我们对14-3-3的一种新的小鼠模型进行了研究，这是一个涉及脑内丰富蛋白质家族，突触功能和精神分裂症的遗传联系。我们发现，抑制14-3-3功能，小鼠大脑损害突触传递，并导致各种行为缺陷，对应于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，在前脑神经元的兴奋性突触中14-3-3信号传导的潜在靶点之一。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独特的工具，阐明精神分裂症相关行为发展背后的突触机制。在这我们将1）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的影响小鼠神经元兴奋性、突触生理学和同步网络活动的功能障碍脑;和3）描绘14-3-3依赖性调节的细胞和分子机制，突触NMDA受体。这项研究涵盖了我们三个实验室的专业知识，实力和现有资源。结果这项研究将大大推进我们对14-3-3蛋白的突触功能及其在精神疾病中的作用。