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

描述（由申请人提供）：已显示个体神经元响应于网络活动而稳态地改变其兴奋性连接的强度： 慢性不活动诱导突触功效的代偿性增加，而慢性过度活动诱导突触功效的代偿性降低。事实上，稳态突触可塑性（HSP）的负反馈回路被认为是神经元和神经网络稳定性所必需的。然而，被认为是学习和记忆基础的联想或赫布突触可塑性，被认为是通过突触强度的正反馈变化进行的。因此，尚不清楚稳态突触适应如何在已建立的神经元网络中发生而不威胁赫布信息存储。利用形态学和功能分析，我们已经观察到，HSP在成熟的海马神经元在体外优先发生在近端突触。近端适应的机制包括活动依赖性的多叶树突棘的形成和消除，这些树突棘在形态学、生化学和组织学上类似于“多刺的赘生物”。多刺的赘生物是体内CA3锥体神经元的复杂近端棘，接受来自同样大的突触前齿状回（DG）苔藓纤维终末的神经支配。DG和CA 3神经元之间高度特化的突触的精确功能自世纪前被发现以来一直是个谜。我们假设，这些突触是稳态的“增益控制位点”，不仅成熟的海马CA3神经元，但完整的海马网络。因此，我们建议调查是否稳态突触适应优先发生在苔藓纤维CA3突触。我们将使用一个双管齐下的功能和形态学的方法来测试这一假设在体外和体内。 公共卫生相关性：自稳态调节的概念开创了现代生理学的时代，在过去的15年里才被应用于中枢神经系统，并且仍然有很大的潜力影响我们对神经系统疾病和功能障碍的方法。我们建议，海马电路的稳态调节发生在一个特定的位置，即大，专门的突触之间的齿状回（DG）颗粒细胞和CA3锥体神经元。有趣的是，该区域已被广泛地牵连在癫痫发生，提高了可能性，我们提出的研究将揭示海马电路的正常稳态调节和颞叶癫痫和神经退行性疾病的发病机制失调。

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.