Neurotrophins, spontaneous release, and synaptic growth cascades

神经营养素、自发释放和突触生长级联

• 批准号: 8656824
• 负责人: ROBERT D HAWKINS
• 金额: $ 30.15万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8656824
• 关键词: Address; Alzheimer' s Disease; Aplysia; Autocrine Communication; Back; Brain-Derived Neurotrophic Factor; Cell Culture Techniques; Data; Development; Disease; Dominant-Negative Mutation; Drug Addiction; Feedback; Functional disorder; Growth; Huntington Disease; Image; Injection of therapeutic agent; Learning; Maintenance; Mental Depression; Mental disorders; Methods; Modeling; Motor Neurons; Nervous system structure; Neuromodulator; Neurons; Parkinson Disease; Play; Process; Proteins; Recruitment Activity; Rett Syndrome; Role; Schizophrenia; Sensory; Serotonin; Signal Transduction; Small Interfering RNA; Source; Synapses; Synaptic plasticity; Synaptophysin; System; Testing; Variant; Varicosity; Vesicle; autocrine; nervous system disorder; neurotrophic factor; overexpression; postsynaptic; presynaptic; public health relevance; receptor

DESCRIPTION (provided by applicant): BDNF and other neurotrophins (NTs) have widespread and powerful roles in mammalian nervous system, and are thought to be involved in a number of psychiatric and neurological disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, Rett syndrome, drug addiction, schizophrenia, and depression. However, how NTs function at the cellular and synaptic levels is not well understood. In particular, it is not clear whether they are released from or act on the pre- or postsynaptic neuron. Aplysia sensory-motor neuron synapses in isolated cell culture are an ideal system for addressing those types of questions. An Aplysia BDNF-like NT and its Trk-like receptor have recently been identified and shown to be important for the induction of long-term facilitation (LTF) and growth of presynaptic varicosities. I now propose to use the Aplysia culture system to examine the pre- and postsynaptic roles of ApNT in two learning-related forms of synaptic plasticity, LTF and intermediate-term facilitation (ITF) by the neuromodulator 5HT. NTs do not act in isolation, but are often part of signaling cascades. For example, synaptic growth during development involves a cascade of pre- and postsynaptic changes and back-and-forth signaling by a variety of molecules including NTs and the transmitter itself. Disorders of this synaptic growth cascade are thought to contribute to a number of neurodevelopmental diseases including schizophrenia and Rett syndrome, which also involve NTs. We will investigate the general hypothesis that long-term plasticity involves a similar growth cascade, and specifically examine the role of ApNT and its relationship with spontaneous transmitter release as key players in such a cascade. Recent studies in Aplysia suggest that spontaneous release recruits postsynaptic mechanisms of ITF, and then retrograde signaling contributes to recruiting presynaptic mechanisms of LTF. Preliminary results suggest that ApNT plays an important role and could act as such a retrograde signal, although it might also function as an autocrine or anterograde signal. In addition, spontaneous release may enhance ApNT and ApNT may also enhance spontaneous release, perhaps creating positive feedback loops that would make the cascade more dynamic. To further explore the possible roles of ApNT and spontaneous release in a trans-synaptic signaling cascade leading to long-term synaptic plasticity and growth, we will (1) examine pre- and postsynaptic sources and targets of ApNT during LTF and ITF, (2) examine the roles of ApNT and spontaneous release in the assembly of pre- and postsynaptic components during LTF and ITF, and (3) examine possible interactions between ApNT and spontaneous release during LTF and ITF. These studies may also suggest how dysfunctions of this cascade could contribute to psychiatric and neurological disorders.

描述（由申请人提供）：BDNF和其他神经营养蛋白（NTS）在哺乳动物神经系统中具有广泛而强大的作用，并被认为参与了许多精神病和神经系统疾病，包括阿尔茨海默氏病，包括阿尔茨海默氏病，包括帕金森氏病，帕金森氏病，亨廷顿氏病，亨廷顿氏病，huntington's syndrome syndrome syndrome addiction，schiz and Intedia，Schiz and Intectiz and Intectiz and Intectiz and Distive，Schiz and Distion。但是，NTS在细胞和突触水平上的功能尚未得到充分了解。特别是，目前尚不清楚它们是从释放还是对突触前神经元或对突触后神经元起作用。孤立细胞培养中的尖脂感觉运动神经元突触是解决这些类型问题的理想系统。最近已经鉴定出类似Aplysia BDNF的NT及其TRK样受体，并证明对诱导长期促进（LTF）和突触前静脉曲张的生长很重要。我现在建议使用Aplysia培养系统检查APNT在两种与学习相关的突触可塑性，LTF和中期促进作用（ITF）中，由神经调节剂5HT检查。 NT不孤立起作用，而是信号级联的一部分。例如，发育过程中的突触生长涉及一系列的突触前和突触后变化以及通过包括NTS和发射器本身在内的各种分子来来回信号传导。人们认为这种突触生长级联反应的疾病会导致许多涉及NTS的神经发育疾病，包括精神分裂症和RETT综合征。我们将调查一般假设，即长期可塑性涉及类似的增长级联，并专门研究APNT的作用及其与自发发射器释放的关系，作为这种级联的关键参与者。垂直脂蛋白的最新研究表明，自发释放募集了ITF的突触后机制，然后逆行信号传导有助于募集LTF的突触前机制。初步结果表明，尽管它也可能充当自分泌或顺行信号，但APNT起着重要的作用，并且可以充当这种逆行信号。此外，自发释放可能会增强APNT，并且APNT也可能增强自发释放，也许会产生正反馈环，从而使级联反应更加动态。 To further explore the possible roles of ApNT and spontaneous release in a trans-synaptic signaling cascade leading to long-term synaptic plasticity and growth, we will (1) examine pre- and postsynaptic sources and targets of ApNT during LTF and ITF, (2) examine the roles of ApNT and spontaneous release in the assembly of pre- and postsynaptic components during LTF and ITF, and (3) examine possible LTF和ITF期间的APNT与自发释放之间的相互作用。这些研究还可能表明该级联反应的功能障碍如何导致精神病和神经系统疾病。