Homeostatic regulation of mossy fiber-CA3 synapses in mature hippocampal gain con

成熟海马增益控制中苔藓纤维-CA3突触的稳态调节

• 批准号: 8689192
• 负责人: BN Queenan
• 金额: $ 1.12万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8689192
• 关键词: AMPA Receptors; Acute; Adult; Agonist; Behavior; Biological Assay; Biological Neural Networks; Cells; Chronic; Complex; Confocal Microscopy; Control Locus; Data; Dendritic Spines; Distal; Epilepsy; Epileptogenesis; Excitatory Synapse; Feedback; Fiber; Frequencies; Hippocampus (Brain); Hyperactive behavior; In Vitro; Individual; Information Storage; Learning; Light; Location; Measures; Mediating; Memory; Morphology; Mus; Nerve Degeneration; Neuraxis; Neurologic Dysfunctions; Neurons; Pathogenesis; Physiology; Predisposition; Probability; Proteins; Pyramidal Cells; RNA Interference; Recycling; Regulation; Scaffolding Protein; Slice; Structure; Synapses; Synaptic plasticity; Temporal Lobe Epilepsy; Testing; Up-Regulation; Vertebral column; afadin; base; biocytin; cell type; dentate gyrus; granule cell; hippocampal pyramidal neuron; immunocytochemistry; in vivo; metabotropic glutamate receptor 2; mossy fiber; nerve supply; nervous system disorder; novel; patch clamp; postsynaptic; presynaptic; prevent; reconstruction; response; transmission process; vector

DESCRIPTION (provided by applicant): Individual neurons have been shown to homeostatically alter the strength of their excitatory connections in response to network activity: chronic inactivity induces compensatory increases in synaptic efficacy, while chronic hyperactivity induces compensatory decreases in synaptic efficacy. In fact, the negative feedback loops of homeostatic synaptic plasticity (HSP) are thought to be essential for the stability of neurons and neural networks. However, associative, or Hebbian, synaptic plasticity, which is thought to underlie learning and memory, is proposed to proceed via positive feedback-based changes in synaptic strength. It is therefore unclear how homeostatic synaptic adaptation can occur in established neuronal networks without threatening Hebbian information storage. Using both morphological and functional analysis, we have observed that HSP in mature hippocampal neurons in vitro occurred preferentially at proximal synapses. The mechanism of proximal adaptation consisted of the activity-dependent formation and elimination of large, multi-lobed dendritic spines which morphologically, biochemically, and pharmacologically resemble "thorny excrescences." Thorny excrescences, the complex proximal spines of CA3 pyramidal neurons in vivo, receive innervation from equally large presynaptic dentate gyrus (DG) mossy fiber terminals. The precise function of the highly specialized synapses between DG and CA3 neurons has remained enigmatic since their discovery over a century ago. We hypothesize that these synapses are the homeostatic "gain control locus" for not only mature hippocampal CA3 neurons, but for intact hippocampal networks. We therefore propose to investigate whether homeostatic synaptic adaptation occurs preferentially at mossy fiber-CA3 synapses. We will use a two-pronged functional and morphological approach to test this hypothesis both in vitro and in vivo.

描述(由申请人提供)：单个神经元已被证明可以自稳态地改变其兴奋性连接的强度，以响应网络活动： 慢性不活动导致突触效能的代偿性增加，而慢性多动导致突触效能的代偿性降低。事实上，稳态突触可塑性(HSP)的负反馈环对于神经元和神经网络的稳定是必不可少的。然而，联想或Hebbian突触可塑性被认为是学习和记忆的基础，它被认为是通过基于正反馈的突触强度变化来进行的。因此，尚不清楚如何在不威胁Hebbian信息存储的情况下，在已建立的神经元网络中发生动态平衡突触适应。通过形态和功能分析，我们观察到在体外成熟的海马神经元中，HSP优先发生在突触近端。近端适应的机制包括依赖活动的大的、多叶的树突棘的形成和消除，这些树突棘在形态上、生化上和药理上类似于“刺突”。棘突是活体CA3锥体神经元复杂的近端棘突，从同样大的突触前齿状回(DG)苔藓纤维终末接受神经支配。自从一个多世纪前发现DG和CA3神经元之间高度专业化的突触以来，它们的确切功能一直是个谜。我们假设这些突触不仅对于成熟的海马CA3神经元，而且对于完整的海马网，都是动态平衡的“增益控制点”。因此，我们建议调查是否动态平衡突触适应优先发生在苔藓纤维-CA3突触。我们将使用功能和形态双管齐下的方法在体外和体内验证这一假说。