Control of Axon Initial Segment in Epilepsy

癫痫轴突起始段的控制

基本信息

批准号：
10183360
负责人：
Attila Losonczy
金额：
$ 67.36万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-15 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10183360
关键词：
Action Potentials Address Adult Anatomy Antiepileptic Agents Area Axon Behavioral Calcium Cell model Cells Chronic Cognitive Cognitive deficits Computer Models Coupling Development Electroencephalography Electron Microscopy Electrophysiology (science)Epilepsy Functional Imaging Future Gap Junctions Generations Hippocampus (Brain)Human Hyperactivity Image Imaging Techniques Impairment In Vitro Interneurons Intervention Kinetics Knowledge Label Mediating Membrane Potentials Modeling Mus Outcome Measure Pathologic Patients Pattern Pharmacotherapy Pilocarpine Play Population Population Dynamics Positioning Attribute Probability Process Production Property Pyramidal Cells Refractory Regulation Resistance Resolution Rodent Role Seizures Signal Transduction Synapses Synaptic Transmission Techniques Temporal Lobe Epilepsy Testing Therapeutic Transgenic Organisms behavioral outcome brain cell cell type comorbidity efficacy evaluation gamma-Aminobutyric Acid in vivo in vivo calcium imaging kainate mouse model novel optogenetics postsynaptic recruit response side effect treatment strategy voltage

项目摘要

Temporal lobe epilepsy (TLE) is the most common epilepsy in adults, and it is frequently refractory to current anti-epileptic drugs, with treatments often exerting a variety of debilitating side effects. A major barrier for the development of novel treatment strategies is our insufficient understanding of the precise cellular and circuit mechanisms underlying TLE. A centrally important but unresolved question in TLE concerns the mechanisms underlying the excessive, dysregulated production of action potentials at the axon initial segment (AIS) of excitatory principal cells (PCs). Synaptic control of AIS is provided by a unique, evolutionarily conserved, GABAergic cell-type, the axo-axonic cells (AACs). AACs form synaptic contacts exclusively with the AIS of PCs, placing AACs in a strategic position to control action potential generation. However, due to technical limitations, our knowledge about the in vivo function and regulation of AACs in the normal and epileptic hippocampus has been extremely limited. Here we propose to employ a combination of recent technical breakthroughs to test hypotheses about the in vivo functional effects, activity dynamics and efficacy of AAC- mediated control of AIS in mouse models of chronic TLE. The planned project will also determine if it is possible to mitigate epilepsy-related pathologically hyperactive circuits and cognitive deficits through interventions selectively directed at the AAC-dependent, endogenous GABAergic processes regulating AIS in chronic epilepsy. The proposed project aims to fill a major knowledge gap and address long-standing controversies concerning the interneuronal regulation of AIS in epilepsy by leveraging expertise in novel large- scale, high-resolution in vivo functional imaging techniques in combination with advanced electrophysiological, behavioral, optogenetic and computational modeling techniques in the CA1 region of the mouse hippocampus. It is anticipated that defining the function, regulation and therapeutic potential of AACs in TLE will have a significant impact by advancing our understanding of key circuit control mechanisms in chronic epilepsy and aid the future development of novel anti-epileptic treatment strategies.

颞叶癫痫（TLE）是成人中最常见的癫痫，目前的治疗通常难以治愈。抗癫痫药物，其治疗常常会产生各种使人衰弱的副作用。的一个主要障碍开发新的治疗策略是我们对精确的细胞和回路了解不足 TLE 的机制。 TLE 中一个重要但尚未解决的问题涉及机制轴突起始段（AIS）动作电位产生过度、失调的潜在原因兴奋性主细胞（PC）。 AIS 的突触控制是由一种独特的、进化上保守的、 GABA 能细胞类型，轴突细胞 (AAC)。 AAC 专门与 AIS 形成突触接触 PC，将 AAC 置于控制动作电位生成的战略位置。但由于技术原因局限性，我们对 AAC 在正常和癫痫患者体内功能和调节的了解海马体已经极其有限。在这里，我们建议结合最新的技术测试有关 AAC 体内功能效应、活性动力学和功效的假设的突破介导的慢性 TLE 小鼠模型中 AIS 的控制。计划的项目还将确定是否可以通过以下方式减轻癫痫相关的病理性过度活跃回路和认知缺陷选择性针对 AAC 依赖性、内源性 GABA 能过程调节 AIS 的干预措施慢性癫痫。拟议项目旨在填补重大知识空白并解决长期存在的问题通过利用新型大分子的专业知识，关于癫痫中 AIS 的神经元间调节的争议规模、高分辨率体内功能成像技术与先进的电生理学相结合，小鼠海马 CA1 区域的行为、光遗传学和计算建模技术。预计，定义 AAC 在 TLE 中的功能、调节和治疗潜力将产生深远的影响。通过增进我们对慢性癫痫关键回路控制机制的理解，产生重大影响帮助未来开发新型抗癫痫治疗策略。