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

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。 与公共健康相关：开创了现代生理学时代的动态平衡调节的概念，在过去的15年里只应用于中枢神经系统，仍然具有巨大的潜力来影响我们处理神经紊乱和功能障碍的方法。我们认为，海马环路的动态平衡调节发生在一个特定的位置，即齿状回颗粒细胞和CA3锥体神经元之间的大型、专门化突触。有趣的是，这一区域被广泛地与癫痫的发生有关，这增加了我们提出的研究将有助于阐明海马回路的正常内稳态调节以及它们在颞叶癫痫和神经退行性变中的失调的发病机制。

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. PUBLIC HEALTH RELEVANCE: The notion of homeostatic regulation, which ushered in the era of modern physiology, has only been applied to the central nervous system within the last 15 years and still has great potential to influence our approach to neurological disorders and dysfunction. We propose that homeostatic regulation of hippocampal circuits occurs at a specific location, namely the large, specialized synapses between dentate gyrus (DG) granule cells and CA3 pyramidal neurons. Intriguingly, this region has been extensively implicated in epileptogenesis, raising the possibility that our proposed studies will shed light on both the normal homeostatic regulation of hippocampal circuits and the pathogenesis of their disregulation in temporal lobe epilepsy and neurodegeneration.