REGULATION OF NEUROTRANSMISSION AND BEHAVIOR

神经传递和行为的调节

• 批准号: 6266919
• 负责人: MICHAEL COLIN WILSON
• 金额: $ 25.69万
• 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 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6266919
• 关键词: attention deficit disorder; behavioral /social science research tag; behavioral genetics; developmental neurobiology; disease /disorder model; exocytosis; genetically modified animals; laboratory mouse; mutant; nerve /myelin protein; neural transmission; neurotransmitter transport; pharmacogenetics; protein biosynthesis; protein isoforms; psychopharmacology; synapses; synaptic vesicles; synaptosomes; tissue /cell culture

DESCRIPTION: (applicant's abstract) Proper function of the nervous system requires the development and maintenance of appropriate neuronal connectivity and effective communication that is largely mediated by chemical synapses. Deficits in synaptic connectivity, resulting from genetic or epigenetic abnormalities revealed either during development or after acute pharmacological or environmental insult, are likely to contribute significantly to impaired brain function. Regulated exocytosis of classical neurotransmitters, as well as neuropeptides and modulatory neurotrophic factors is proposed to underlie the necessary presynaptic input for effective communication between neurons. The overall goal of the research of this laboratory is to gain a better understanding of the molecular mechanisms which control neuroexocytosis. Moreover, implicit in these studies is the general hypothesis that presynaptic regulation of neurotransmitter release can modulate brain development and function, and consequently that deficiencies in this molecular machinery can play at least a part in the cognitive and behavioral impairments of neuropsychiatric disorders. To address these issues, we have focused on the protein SNAP-25, which we propose plays a regulatory role, as well as its more well-defined part as an integral structural component of the exocytotic protein machinery necessary for vesicle fusion and neurotransmitter release. Our investigations make use of SNAP-25 null and hypomorphic mouse mutants which we have developed in the previous funding of this grant. In Specific Aim 1 experiments are designed to use Snap25-/- mice to determine the role of neuroexocytosis in axon stabilization and synapse formation. Specific Aim 2 will use replication defective viral expression systems and Snap25-/- cultured neurons to examine role of sequences that are postranslationally modified and distinguish developmentally regulated SNAP-25 isoforms. Specific Aim 3 addresses the hypothesis of whether the developmental switch in SNAP-25 isoforms underlines the maturation of synaptic transmission by electrophysiological and neurochemical measurements of SNAP-25b hypomorph mutants. Finally in Specific Aim 4, experiments are designed to examine whether Snap25 heterozygotes that express reduced levels of SNAP-25 are more susceptible to psychotomimetic drugs and thus are a model of genetic vulnerability. If successful this investigation will shed light on the selective roles of SNAP-25 isoforms, the roles they play in the synaptic plasticity required for normal brain function, and how abnormalities in presynaptic mechanisms of neurotransmission may be involved in neuropsychiatric disease.

描述：(申请人摘要) 神经系统的正常功能需要发育和维持 适当的神经元连接和有效的沟通，即 主要由化学突触调节。突触连接的缺陷， 由遗传或表观遗传异常引起的 在急性药物或环境侮辱后，很可能发生 对大脑功能受损有显著影响。调节的胞吐作用 经典的神经递质，以及神经肽和调节剂 神经营养因子被认为是必要的突触前输入的基础 用于神经元之间的有效交流。这项研究的总体目标 是为了更好地了解分子 控制神经胞吐的机制。此外，在这些研究中隐含着 是一个普遍的假设，即突触前调节神经递质 释放可以调节大脑的发育和功能，因此 这种分子机制的缺陷至少可以在 神经精神障碍的认知和行为障碍。致信地址 这些问题，我们已经集中在蛋白质SNAP-25，我们建议发挥作用 监管角色，以及其作为一个整体的更明确的部分 囊泡所必需的胞吐蛋白机械的结构组成 融合和神经递质释放。我们的调查使用了SNAP-25 我们在上一篇文章中开发的无效和亚型小鼠突变体 为这笔赠款提供资金。在特定的目标中，1个实验旨在使用 Snap25-/-小鼠确定神经胞吐在轴突稳定中的作用 和突触的形成。特定目标2将使用复制缺陷病毒 表达系统和Snap25/培养神经元检测序列的作用 翻译后修饰的，区别于发育调节的 Snap-25亚型。具体目标3解决了这样的假设，即 SNAP-25亚型的发育转换强调突触的成熟 SNAP-25b的电生理和神经化学传递 低畸型变种人。最后，在具体目标4中，设计实验以 检查表达SNAP-25水平降低的Snap25杂合子是否 更容易受到精神分裂药物的影响，因此是一种遗传模型 脆弱性。如果成功，这项调查将揭示 SNAP-25亚型的选择性作用及其在突触中的作用 正常大脑功能所需的可塑性，以及 突触前神经传递机制可能参与神经精神病学 疾病。