Control of Axon Initial Segment in Epilepsy

摘要颞叶癫痫(TLE)是成人最常见的癫痫，常为难治性癫痫。 抗癫痫药物，治疗往往会产生各种衰弱的副作用。一个主要的障碍是 开发新的治疗策略是我们对精确的细胞和电路的了解不足 TLE的潜在机制。TLE中的一个核心重要但尚未解决的问题涉及机制 轴突起始节段(AIS)动作电位过度、失调产生的基础 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与AIS形成独有的突触联系 PC，将AAC置于控制动作电位产生的战略位置。然而，由于技术上的原因 我们对正常人和癫痫患者AACs体内功能和调节的认识 海马体一直非常有限。在这里，我们建议结合使用最新的技术 AAC体内功能效应、活性动力学和有效性假说的突破性进展 慢性TLE小鼠模型中AIS的介导性控制。计划中的项目也将决定它是否 可能通过以下方式减轻癫痫相关的病理性过度活跃的回路和认知缺陷 选择性地针对AAC依赖的内源性GABA能过程调节AIS的干预 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 关于AIS在癫痫中的神经元间调节的争议通过利用新的大脑神经系统的专业知识 大规模、高分辨率的活体功能成像技术与先进的电生理相结合， 小鼠海马区CA1区的行为、光遗传和计算建模技术。 预计在TLE中确定AAC的功能、调节和治疗潜力将具有 通过提高我们对慢性癫痫和癫痫的关键电路控制机制的理解，产生重大影响 有助于未来新的抗癫痫治疗策略的发展。

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.