The role of intrinsic cellular excitability in homeostatic plasticity of developi

内在细胞兴奋性在发育稳态可塑性中的作用

• 批准号: 8607620
• 负责人: PETER A WENNER
• 金额: $ 8.53万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8607620
• 关键词: Attention; Cells; Chick Embryo; Cognitive; Development; Drug Prescriptions; Egg Shell; Embryo; Embryonic Development; Fetus; Financial compensation; Hour; Impairment; Incidence; Infantile spasms; Interneurons; Left; Life; Mediating; Monitor; Motor; Motor Neurons; Movement; Nature; Neonatal; Neurologic Dysfunctions; Neurons; Population; Process; Receptor Activation; Recovery; Role; Seizures; Signal Transduction; Spinal; Spinal Cord; Staging; Synapses; Synaptic plasticity; System; Testing; Time; Voltage-Gated Potassium Channel; age group; cell growth regulation; gamma-Aminobutyric Acid; in vitro activity; in vivo; insight; neural circuit; public health relevance; transmission process; voltage

DESCRIPTION (provided by applicant): 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 (e.g. cells increase in size). Therefore it is not surprising that the incidence of seizure activity is higher in the neonatal period than in any other age group. Neonatal seizures are often the first indication of neurological dysfunction, and are strong predictors of long-term cognitive and developmental impairment. Understanding the rules and mechanisms that underlie the maturation of network excitability are therefore essential. In the last decade 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) for days, and although activity doesn't homeostatically recover, changes in synaptic strength are in a compensatory direction. Therefore, it is assumed, although untested, that these changes would normally act to recover activity levels following perturbations in vivo. 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 are faster and likely more important in the initial recovery of normal activity levels. The objective of this application is to better understand the role of cellular excitability in the process of homeostatically recovering and maintaining network activity in developing networks. We are proposing to perturb network activity in the living embryo, allow for the homeostatic recovery of activity and assess how changes in cellular excitability contribute to this recovery. This will provide a more realistic, comprehensive understanding of the homeostatic regulation of cellular excitability and its role in maintaining appropriate activity levels and maturing network excitability.

描述(申请人提供)：这是一个非凡的成就，大多数发展中的神经元网络实现了适当水平的兴奋性，在胚胎发育的动态时期，网络的兴奋性面临几个挑战(例如细胞增大)。因此，新生儿期癫痫发作发生率高于任何其他年龄段也就不足为奇了。新生儿癫痫发作通常是神经功能障碍的第一个指征，也是长期认知和发育障碍的强烈预测指标。因此，了解网络兴奋性成熟背后的规则和机制是至关重要的。在过去的十年中，出现了一个令人兴奋的新领域，它为理解网络为了实现适当的活动水平而遵循的规则提供了关键的见解。许多研究现在表明，网络通过调节突触强度(自稳突触可塑性)，将活动水平维持在适当的范围内。这些研究中的绝大多数已经在体外(培养)阻止了网络活动几天，尽管活动不是自稳恢复的，但突触强度的变化是在补偿方向上的。因此，我们假设，尽管未经测试，这些变化通常会在体内受到干扰后恢复活动水平。细胞内在兴奋性(细胞对突触输入的反应性)的代偿性变化也可能有助于动态平衡过程，尽管这些变化远没有突触补偿受到关注。我们发现，细胞兴奋性的变化更快，在正常活动水平的最初恢复中可能更重要。这项应用的目的是为了更好地了解细胞兴奋性在动态平衡恢复和维持网络活动发展过程中的作用。我们建议扰乱活胚胎中的网络活动，允许活动的动态平衡恢复，并评估细胞兴奋性的变化如何有助于这种恢复。这将对细胞兴奋性的动态平衡调节及其在维持适当的活动水平和成熟的网络兴奋性中的作用提供更现实、更全面的理解。