Control of Axon Initial Segment in Epilepsy

癫痫轴突起始段的控制

• 批准号: 10600120
• 负责人: Attila Losonczy
• 金额: $ 64.7万
• 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/10600120
• 关键词: Action Potentials; Address; Adult; Anatomy; Antiepileptic Agents; Area; Axon; Behavioral; Calcium; Cell model; Cells; Chronic; Cognitive; Cognitive deficits; Computer Models; Coupling; Dedications; Development; Electroencephalography; Electron Microscopy; Electrophysiology (science); Epilepsy; Functional Imaging; Future; Gap Junctions; Generations; Hippocampus; 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）是成年人中最常见的癫痫 抗癫痫药，治疗通常会产生各种使人衰弱的副作用。一个主要的障碍 新型治疗策略的发展是我们对精确的细胞和电路的理解 TLE的机制。在TLE中，一个非常重要但尚未解决的问题涉及机制 在轴突初始细分（AIS）处的过度，失调的作用电位产生的基础 兴奋性主细胞（PC）。 AIS的突触控制由独特的，进化保守的， GABA能细胞类型，轴轴突细胞（AAC）。 AACS仅与AIS的AIS形成突触接触 PC，将AAC置于控制动作潜在产生的战略位置。但是，由于技术 局限性，我们对正常和癫痫病中AAC的体内功能的了解和调节 海马非常有限。在这里，我们建议采用最近的技术组合 突破性测试有关体内功能效应，活性动力学和AAC-功效的假设 慢性TLE小鼠模型中AI的介导对照。计划的项目还将确定是否是 可以通过减轻与癫痫相关的病理性过度活跃电路和认知缺陷 干预措施选择性针对AAC依赖性的内源性GABA能量，以调节AIS 慢性癫痫。拟议的项目旨在填补主要的知识差距，并解决长期存在 关于癫痫中AIS的神经元调节的争议，利用新型大型的专业知识， 比例，高分辨率在体内功能成像技术与晚期电生理学结合 小鼠海马的CA1区域中的行为，光遗传学和计算建模技术。 可以预料，定义AAC在TLE中的功能，调节和治疗潜力将具有 通过促进我们对慢性癫痫和关键电路控制机制的理解和 帮助未来的新型抗癫痫治疗策略的发展。