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: 8041865
• 负责人: PETER A WENNER
• 金额: $ 30.52万
• 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/8041865
• 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 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; 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. PUBLIC HEALTH RELEVANCE: We are testing the possibility that a spontaneous network activity that is expressed in embryonic neural circuits regulates the intrinsic cellular excitability in motor and interneurons. In this way, we are studying the maturation of embryonic network excitability.

描述（由申请人提供）：这是一项非凡的成就，大多数正在发育的神经网络在胚胎发育的动态时期达到适当的兴奋性水平，此时网络的兴奋性面临着一些挑战（例如细胞的大小增加）。因此，癫痫发作的发生率在新生儿期高于其他任何年龄组，这并不奇怪。新生儿癫痫发作通常是神经功能障碍的第一个指征，是长期认知和发育障碍的有力预测因素。因此，了解网络兴奋性成熟背后的规则和机制至关重要。在过去的十年里，一个令人兴奋的新领域出现了，它为理解网络为了达到适当的活动水平而遵循的规则提供了关键的见解。许多研究表明，神经网络通过调节突触强度（稳态突触可塑性）来将活动水平维持在一个适当的范围内。这些研究绝大多数在体外（培养）阻断网络活动数天，尽管活动不能自稳态恢复，但突触强度的变化是代偿方向的。因此，虽然未经测试，但假设这些变化通常会在体内扰动后恢复活动水平。细胞内在兴奋性（细胞对突触输入的反应）的代偿性变化也可能有助于稳态过程，尽管这些变化受到的关注远远少于突触代偿。我们发现，细胞兴奋性的变化更快，可能在正常活动水平的初始恢复中更重要。本应用的目的是为了更好地理解细胞兴奋性在动态恢复和维持发育中的网络活动过程中的作用。我们建议在活胚胎中干扰网络活动，允许活动的稳态恢复，并评估细胞兴奋性的变化如何促进这种恢复。这将提供一个更现实、更全面的理解细胞兴奋性的稳态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。