REGULATION OF NEUROTRANSMISSION AND BEHAVIOR

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， 很大程度上由化学突触介导。突触连接的缺陷， 由遗传或表观遗传异常引起， 急性药物或环境损伤后， 对大脑功能受损有很大影响调节胞吐作用 经典的神经递质，以及神经肽和调节 神经营养因子被认为是突触前输入的基础 神经元之间的有效沟通。研究的总体目标 是为了更好地了解 控制神经胞吐作用的机制。此外，在这些研究中， 是一个普遍的假设， 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。解决 针对这些问题，我们重点关注了蛋白质SNAP-25，我们认为它发挥着重要作用。 监管作用，以及其更明确的一部分，作为一个整体 囊泡所必需的胞吐蛋白机械的结构成分 融合和神经递质释放。我们的调查利用SNAP-25 无效和亚纯型小鼠突变体，我们已经开发了在以前的 这笔赠款的资金。在具体目标1中，实验旨在使用 Snap 25-/-小鼠以确定神经胞吐作用在轴突稳定中的作用 和突触的形成Specific Aim 2将使用复制缺陷型病毒 表达系统和Snap 25-/-培养的神经元，以检查序列的作用 在翻译后被修改， SNAP-25同种型。具体目标3涉及的假设是， SNAP-25亚型的发育转换强调了突触的成熟， 通过SNAP-25 b的电生理学和神经化学测量的传递 亚型突变体最后，在具体目标4中，实验设计为 检查表达降低水平的SNAP-25的Snap 25杂合子是否 更容易受到拟精神病药物的影响，因此是一种遗传模型， 易损性.如果调查成功， SNAP-25亚型的选择性作用，它们在突触中的作用， 正常大脑功能所需的可塑性，以及大脑中的异常是如何产生的。 神经传递的突触前机制可能参与神经精神 疾病

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.