Regulation of Neurotransmission and Behavior

神经传递和行为的调节

• 批准号: 6823955
• 负责人: MICHAEL COLIN WILSON
• 金额: $ 33.57万
• 依托单位: UNIVERSITY OF NEW MEXICO
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-03-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6823955
• 关键词: behavioral /social science research tag; behavioral genetics; cell cell interaction; developmental neurobiology; electrophysiology; exocytosis; genetically modified animals; green fluorescent proteins; laboratory mouse; nerve /myelin protein; neural plasticity; neural transmission; neurons; neurotransmitter transport; protein biosynthesis; protein isoforms; receptor expression; synapses; synaptic vesicles; synaptosomes; terminal nick end labeling; tissue /cell culture

DESCRIPTION (provided by applicant): The development, maintenance and control of neurotransmitter secretion at chemical synapses underlie the neuronal communication necessary for the proper function of the nervous system. Deficits in synaptic transmission and connectivity, resulting from genetic or epigenetic abnormalities revealed during development, are likely to contribute to impaired brain function. In particular, regulated exocytosis of classical neurotransmitters and neuropeptides is a key factor that underlies the necessary presynaptic input for effective communication between neurons. The overall goal of the research of our laboratory is to gain a better understanding of the molecular, cellular and developmental mechanisms which control neuroexocytosis. Our hypothesis is that the developmental regulation of the composition of the molecular machinery responsible for membrane trafficking and vesicular fusion for neurotransmission is instrumental in developing how neurons communicate during the initial contact and formation of synapses, and ultimately in sculpting the synaptic physiology of the mature nervous system. To address this hypothesis, we have focused on the protein SNAP-25, a key element of the SNARE complex mediating membrane fusion for transmitter release. We propose that the transition from a constitutively expressed homologue, SNAP-23, to the regulated expression of SNAP-25 isoforms plays a key role in mediating vesicle fusion for growing axons to functional synapses capable of evoked neurotransmitter release and synaptic activity. Our investigations make use of Snap25 gene mutants in the mouse developed through previous funding of this grant and a conditional mutation to be generated during the present period. In Specific Aim 1, experiments are designed to examine the role of spontaneous neurotransmitter release in cultured cells and fetal brain development using Snap25 null mutants. In Specific Aim 2, we will examine whether the switch in SNAP-25 isoforms is required for maturation of synaptic transmission during postnatal development using a mutation that prolongs overexpression of the SNAP-25a isoform. Finally in Specific Aim 3, we will extend our analysis to study later steps of synaptogenesis and synaptic maturation that occur after birth, and in the long-term neurodegenerative processes, by investigating synaptic functions of a conditional Snap25 gene mutation controlled by inducible expression of Cre recombinase. If successful, these investigations will shed light on the roles of SNAP-25 and its isoforms during development and for synaptic plasticity required for normal brain function, and how abnormalities in presynaptic mechanisms of neurotransmission are involved in neuropsychiatric disease.

描述（由申请人提供）： 化学突触处神经递质分泌的发展、维持和控制是神经系统正常功能所必需的神经元通信的基础。发育过程中发现的遗传或表观遗传异常导致的突触传递和连接缺陷可能会导致脑功能受损。特别是，经典的神经递质和神经肽的调节胞吐作用是神经元之间有效通信所必需的突触前输入的关键因素。我们实验室研究的总体目标是更好地了解控制神经胞吐作用的分子、细胞和发育机制。我们的假设是，负责膜运输和囊泡融合的神经传递的分子机制的组成的发育调节是有助于发展神经元如何在最初的接触和突触的形成过程中进行通信，并最终在雕塑成熟的神经系统的突触生理。为了解决这一假设，我们集中在蛋白质SNAP-25，一个关键的SNARE复合物介导的膜融合递质释放的元素。我们建议，从组成型表达的同源物，SNAP-23，SNAP-25亚型的表达调控的过渡起着关键作用，在介导囊泡融合生长轴突的功能性突触能够诱发神经递质释放和突触活动。我们的研究利用了通过先前的资助开发的小鼠中的Snap 25基因突变体以及在此期间产生的条件突变。在特定目标1中，实验设计用于使用Snap 25无效突变体检查培养细胞和胎儿脑发育中自发神经递质释放的作用。在具体目标2中，我们将研究是否需要在SNAP-25异构体的开关在出生后发育过程中使用突变，过度表达SNAP-25 a异构体的突触传递的成熟。最后，在具体目标3中，我们将扩展我们的分析，研究出生后发生的突触发生和突触成熟的后期步骤，以及在长期的神经退行性过程中，通过研究由Cre重组酶诱导表达控制的条件性Snap 25基因突变的突触功能。如果成功，这些研究将揭示SNAP-25及其亚型在发育过程中的作用，以及正常脑功能所需的突触可塑性，以及神经传递的突触前机制异常如何参与神经精神疾病。