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

内在细胞兴奋性在发育回路稳态可塑性中的作用

• 批准号: 10179498
• 负责人: PETER A WENNER
• 金额: $ 36.25万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-17 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10179498
• 关键词: Affinity; Attention; Behavioral; Biological Models; Calcium; Cells; Chick; Chick Embryo; Data; Development; Egg Shell; Electrophysiology (science); Embryo; Embryonic Development; Energy Metabolism; Ensure; Financial compensation; Genetic; Glutamates; Grant; Homeostasis; Hour; Image; Intervention; Lead; Left; Living Wills; Maintenance; Mediating; Membrane Potentials; Metabolism; Mitochondria; Mitochondrial Proteins; Molecular; Movement; Mus; Muscle Hypertonia; Myoclonus; Na(+)-K(+)-Exchanging ATPase; Nature; Neonatal; Neurodevelopmental Disorder; Neurons; Organism; Paper; Pharmacology; Play; Population; Process; Proteins; Proteomics; Recovery; Recurrence; Rest; Role; Spinal; Spinal Cord; Synapses; Synaptic plasticity; System; Testing; Tremor; Work; base; insight; mouse model; neural circuit; novel therapeutic intervention; receptor; response; sensor; spasticity; success; voltage

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. 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. An exciting new field has emerged, which provides critical insights to understanding the rules that networks follow in order to achieve appropriate levels of activity. Many studies have now shown that perturbations to network activity trigger changes in synaptic strength which are thought to homeostatically recover and maintain activity levels within an appropriate range. 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. By taking advantage of the accessibility of the chick embryo we have been able to follow an actual homeostatic recovery of activity (embryonic movements). Because of this, we have been able to identify a critical and previously unrecognized homeostatic mechanism where changes in resting membrane potential mediate the initial homeostatic recovery of perturbed activity levels in the living embryonic spinal cord. We will identify the mechanism underlying this compensation in the first aim of the grant. Based on a recent study and our proteomic analysis from our previous grant period, we are proposing to examine an unexpected critical relationship between mitochondrial function and homeostatic plasticity in aim 2. Finally in aim 3 we will carry out this work in the genetically advantageous mouse model system. Our study will identify the mechanisms of homeostatic plasticity in the living system and will begin to elucidate the calcium triggers for these forms of plasticity. The work can instruct pharmacological interventions that ameliorate hyperexcitability associated with neurodevelopmental disorders, and help us better understand the function of homeostatic plasticity.

摘要 这是一项非凡的成就，大多数发展中的神经元网络 达到适当水平的兴奋性，在动态期处于萌芽状态 当网络的兴奋性面临几个挑战时，开发。错误 在这样一个复杂的过程中会导致新生儿兴奋性的改变 脊髓环路，表现为肌阵挛、高张力、反复发作 震颤和痉挛。了解以下规则和机制 因此，网络兴奋性的成熟是至关重要的。一个令人兴奋的新领域 为理解网络规则提供了关键的见解 遵循以达到适当的活动水平。许多研究现在已经 研究表明，对网络活动的干扰会触发突触强度的变化 它们被认为是在体内平衡恢复和维持活动水平的 适当的范围。固有细胞兴奋性的代偿性变化(细胞 对突触输入的反应性)也可能有助于动态平衡过程， 尽管这些变化远没有Synaptic引起的关注 补偿。通过利用鸡胚的可及性，我们 已经能够遵循实际的动态平衡活动恢复(胚胎 运动)。正因为如此，我们已经能够确定一个关键的和 以前未知的静息状态变化的动态平衡机制 膜电位介导扰动活动的初始动态平衡恢复 在活的胚胎脊髓中的水平。我们将确定这一机制 在赠款的第一个目标中，这一补偿的基础。基于最近的一项研究 和我们之前资助期的蛋白质组学分析，我们建议 检查线粒体功能和线粒体功能之间的意外关键关系 目标2中的动态平衡可塑性。最后，在目标3中，我们将在 遗传优势的小鼠模型系统。我们的研究将确定 生命系统中的稳态可塑性的机制，并将开始阐明 钙触发了这些形式的可塑性。这项工作可以指导药理学 改善与神经发育相关的过度兴奋的干预措施 并帮助我们更好地理解体内平衡可塑性的功能。