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: 10593073
• 负责人: PETER A WENNER
• 金额: $ 36.17万
• 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/10593073
• 关键词: Affinity; Attention; Behavioral; Biological Models; Calcium; Cells; Chick; Chick Embryo; Compensation; Data; Development; Egg Shell; Electrophysiology (science); Embryo; Embryonic Development; Energy Metabolism; Ensure; Genetic; Glutamates; Grant; Homeostasis; Hour; Image; Intervention; K ATPase; Left; Living Wills; Maintenance; Mediating; Membrane Potentials; Metabolism; Mitochondria; Mitochondrial Proteins; Molecular; Movement; Mus; Muscle Hypertonia; Myoclonus; Nature; Neonatal; Neurodevelopmental Disorder; Neurons; Organism; Paper; Play; Population; Process; Proteins; Proteomics; Recovery; Recurrence; Rest; Role; Spinal; Spinal Cord; Synapses; Synaptic plasticity; System; Testing; Tremor; Vertebral column; Work; insight; mouse model; neural circuit; novel therapeutic intervention; pharmacologic; 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 大多数正在发展的神经网络都是一项非凡的成就 在胚胎发育的动态时期， 当网络的兴奋性面临几个挑战时，错误 在这样一个复杂的过程中，可能会导致新生儿兴奋性的改变， 脊髓回路，可观察到肌阵挛、张力亢进、复发性 震颤和痉挛。理解作为其基础的规则和机制 因此，网络兴奋性的成熟至关重要。一个令人兴奋的新领域 它为理解网络的规则提供了重要的见解， 以达到适当的活动水平。许多研究表明， 显示了网络活动的扰动触发了突触强度的变化， 它被认为是在一个特定的时间内恢复和维持活动水平。 合适的范围。内在细胞兴奋性的补偿性变化（细胞的 对突触输入的响应性）也可能有助于体内平衡过程， 尽管这些变化受到的关注远不及突触 补偿。通过利用鸡胚的可及性， 已经能够跟踪活动的实际稳态恢复（胚胎的 运动）。正因为如此，我们已经能够确定一个关键的， 以前未被认识到的稳态机制， 膜电位介导扰动活动的初始稳态恢复 在活的胚胎脊髓中。我们会找出 这是补助金的第一个目标。根据最近的一项研究 以及我们在上一个资助期进行的蛋白质组学分析，我们建议 研究线粒体功能与 aim 2稳态可塑性。最后，在目标3中，我们将在 遗传优势小鼠模型系统。我们的研究将确定 在生活系统的稳态可塑性机制，并将开始阐明 钙触发了这些形式的可塑性。本工作可指导药理学 改善与神经发育相关的过度兴奋的干预措施 疾病，并帮助我们更好地理解稳态可塑性的功能。