Control of Axon Initial Segment in Epilepsy

癫痫轴突起始段的控制

• 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
• 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

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，并且其经常对当前的癫痫治疗无效。 抗癫痫药物，其治疗通常会产生各种使人衰弱的副作用。一个主要的障碍， 新的治疗策略的发展是我们对精确的细胞和电路的理解不足， TLE的潜在机制。TLE中一个重要但尚未解决的问题涉及到 神经元轴突起始段（AIS）动作电位过度、失调的基础 兴奋性主细胞（PC）。AIS的突触控制是由一个独特的，进化上保守的， GABA能细胞型，轴突-轴突细胞（AAC）。AAC仅与AIS形成突触接触， PC，将AAC置于控制动作电位产生的战略地位。但由于技术 局限性，我们对正常和癫痫患者体内AAC功能和调节的了解 海马体已经非常有限。在这里，我们建议采用最新的技术组合， 突破，以测试关于AAC的体内功能效应、活性动力学和功效的假设， 在慢性TLE的小鼠模型中介导的AIS控制。计划中的项目还将确定它是否是 可能通过以下方式减轻癫痫相关的病理性多动回路和认知缺陷 干预选择性地针对AAC依赖性，内源性GABA能过程调节AIS， 慢性癫痫拟议的项目旨在填补一个重大的知识空白，并解决长期存在的问题。 关于AIS在癫痫中的神经元间调节的争议，通过利用新的大的专业知识， 大规模、高分辨率的体内功能成像技术结合先进的电生理学， 行为，光遗传学和计算建模技术在小鼠海马CA 1区。 明确AACs在TLE中的功能、调节和治疗潜力，将对TLE的治疗有重要意义。 通过推进我们对慢性癫痫关键回路控制机制的理解， 有助于未来开发新的抗癫痫治疗策略。