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: 8875789
• 负责人: ROBERT D HAWKINS
• 金额: $ 31.5万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8875789
• 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; 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; postsynaptic neurons; presynaptic; presynaptic neurons; 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.

说明（申请人提供）：BDNF和其他神经营养因子（NT）在哺乳动物神经系统中具有广泛和强大的作用，并且被认为与许多精神和神经障碍有关，包括阿尔茨海默病、帕金森病、亨廷顿病、Rett综合征、药物成瘾、精神分裂症和抑郁症。然而，NT在细胞和突触水平上的功能还不清楚。特别是，尚不清楚它们是否从突触前或突触后神经元释放或作用于突触前或突触后神经元。分离细胞培养中的感觉运动神经元突触是解决这些类型问题的理想系统。最近发现了一种神经营养因子样神经营养因子及其Trk样受体，它们在诱导长时程易化（LTF）和突触前静脉曲张生长中起重要作用。现在，我建议使用的Aaplasia文化系统来检查前和突触后的作用，ApNT在两个学习相关的形式的突触可塑性，LTF和中期促进（ITF）的神经调节剂5 HT。 NT并不是孤立地起作用，而是信号级联的一部分。例如，发育过程中的突触生长涉及突触前和突触后变化的级联反应，以及包括NT和递质本身在内的各种分子的来回信号传导。这种突触生长级联的紊乱被认为是导致许多神经发育疾病的原因，包括精神分裂症和Rett综合征，这些疾病也涉及NT。我们将调查的一般假设，即长期可塑性涉及一个类似的增长级联，并特别检查的作用，ApNT及其与自发递质释放的关系，在这样的级联的关键球员。最近的研究表明，自发释放招募ITF的突触后机制，然后逆行信号有助于招募LTF的突触前机制。初步结果表明，ApNT起着重要的作用，可以作为这样一个逆行信号，虽然它也可能作为一个自分泌或顺行信号。此外，自发释放可能会增强ApNT，ApNT也可能会增强自发释放，可能会产生正反馈回路，使级联反应更具动态性。 为了进一步探索ApNT和自发释放在导致长期突触可塑性和生长的跨突触信号级联中的可能作用，我们将（1）检查LTF和ITF期间ApNT的突触前和突触后来源和靶点，（2）检查LTF和ITF期间ApNT和自发释放在突触前和突触后成分组装中的作用，（3）研究ApNT与LTF和ITF自发释放之间可能的相互作用。这些研究还可能表明，这一级联反应的功能障碍如何导致精神和神经疾病。