The role of intrinsic cellular excitability in homeostatic plasticity of developing circuits

摘要 这是一个非凡的成就，大多数发展中的神经网络实现了一个 适当的兴奋性水平，在胚胎发育的动态时期， 是对网络兴奋性的几个挑战。因此，毫不奇怪， 新生儿期的网状过度兴奋发生率高于其他年龄 组在这样一个复杂的过程中的错误可能会导致新生儿兴奋性的改变， 脊髓回路，其可以在行为上观察到肌阵挛、张力亢进、复发性震颤，以及 痉挛理解网络成熟的规则和机制 因此，兴奋性至关重要。最近，一个令人兴奋的新领域出现了，它提供了 关键的见解，以了解网络遵循的规则，以实现适当的 活动水平。现在许多研究表明，网络稳态维持活动， 通过调节突触强度（稳态突触）， 可塑性）。这些研究中的绝大多数已经在体外（培养）阻断了网络活动。 系统），突触强度的变化是在一个补偿的方向。 内在细胞兴奋性的补偿性变化（细胞对突触输入的反应） 也可能有助于稳态过程，尽管这些变化已经受到了很大的影响。 比突触补偿更少的注意力。我们发现细胞兴奋性的变化 介导胚胎脊髓中扰动活动水平的初始稳态恢复， 线.本应用程序的目的是更好地了解作用和机制 在发育过程中细胞兴奋性和突触强度的潜在稳态变化 电路.我们建议在生活中以更现实的方式扰乱网络活动 胚胎，允许活动的稳态恢复，然后进行全面的 评估介导启动、信号传导和表达的蛋白质， 兴奋性和突触强度的代偿性变化。该项目将提供更多 广泛的，现实的理解稳态可塑性，并确定其在成熟的作用 网络的兴奋性。此外，这项研究将确定每种形式的蛋白质， 稳态可塑性，并因此提供了治疗靶点， 兴奋过度我们的方法引入了一种新的方法，将阐明 一个分子网络，它将识别与人类疾病相关的基因， 了解稳态可塑性的功能。

Abstract It is an extraordinary accomplishment that most developing neuronal networks achieve an appropriate level of excitability, during a dynamic period of embryonic development when there are several challenges to a network's excitability. Therefore, it is not surprising that the incidence of network hyperexcitability is higher in the neonatal period than in any other age group. Errors in such a complicated process can lead to alterations in the excitability of neonatal spinal circuit, which can be observed behaviorally as myoclonus, hypertonia, recurrent tremor, and spasticity. Understanding the rules and mechanisms that underlie the maturation of network excitability are therefore essential. Recently, an exciting new field has emerged that provides critical insights to understanding the rules that networks follow in order to achieve appropriate levels of activity. Many studies have now shown that networks homeostatically maintain activity levels within an appropriate range by adjusting synaptic strength (homeostatic synaptic plasticity). The vast majority of these studies have blocked network activity in vitro (culture systems) for days, and changes in synaptic strength are in a compensatory direction. Compensatory changes in intrinsic cellular excitability (cell's responsiveness to synaptic input) also likely contribute to the homeostatic process, although these changes have received far less attention than synaptic compensations. We have found that changes in cellular excitability mediate the initial homeostatic recovery of perturbed activity levels in the embryonic spinal cord. The objective of this application is to better understand the role and mechanisms underlying homeostatic changes in cellular excitability and synaptic strength in the developing circuit. We are proposing to perturb network activity in a more realistic manner in the living embryo, allow for the homeostatic recovery of activity, and then carry out a comprehensive assessment of the proteins that mediate the initiation, signaling, and expression of compensatory changes in excitability and synaptic strength. The project will provide a more extensive, realistic understanding of homeostatic plasticity, and define its role in the maturation of network excitability. Further, the study will identify proteins underlying each form of homeostatic plasticity, and therefore provide therapeutic targets for conditions of hyperexcitability. Our approach introduces a new method into the homeostatic field that will elucidate a molecular network that will identify genes that associate with human disease, and help us better understand the function of homeostatic plasticity.