CMA: Network plasticity in acquired epileptogenesis

颞叶癫痫(TLE)是成人中最常见的癫痫形式，也是老年人残疾的主要来源 退伍军人人数，因为它经常是由战时头部受伤造成的。超过三分之一的TLE患者没有 对抗惊厥药物有反应，许多人不适合癫痫手术。因此，新的 需要进行治疗，以防止癫痫在最初的侮辱后发展。然而，这些机制 导致癫痫发作期后的直接癫痫持续状态(SE)仍较差 明白了。对这些机制的深入和准确的理解对于制定干预措施至关重要 可以治疗颞叶癫痫，没有药物的副作用，也没有大手术的潜在残疾 切除手术。为了确定SE后最早时段内特定小区类型的网络动态变化， 我们开发了一种微型显微镜，它完全与高通道集成在一起 细胞外电生理记录仪(E-SCOPE)。我们假设超同步发射 小白蛋白阳性(PV+)和生长抑素+(SOM+)中间神经元接合进行性降低 在侮辱后的致痫期间出现。我们还假设这些病理回路 兴奋性神经元和抑制性神经元在200-400赫兹的高频下都可以很容易地观察到动力学。 振荡(HFO)已被证明是高兴奋性癫痫回路的生物标志物。在目标1中，我们将 测量在病理性快速波动和生理性波动期间PV+和SOM+神经元如何被激活 尖波在致痫期间产生涟漪。在目标2中，我们将测量空间编码的精度 通过兴奋性神经元和生理尖波波动期间集合的重新激活和 病理性的快速涟漪贯穿致痫时期。此信息对于识别细胞至关重要 预防癫痫发生的干预措施的具体目标。总体战略：我们的总体目标 协作优点建议是确定海马区和新皮质回路的关键变化， 在最初的侮辱后，会促进癫痫和认知功能障碍的发展。其他建议的目的： 1.Wasterlain将使用免疫细胞化学技术，包括EM免疫细胞化学，来量化变化 在突触和突触周围间隙的GABA受体表达。2.奈勒将使用体外切片 膜片钳记录、光遗传学和计算模型来了解功能连接是如何 不同中间神经元类型在这一关键时期的变化。3.斯米尔纳基斯将结合使用 电生理技术和体内介观双光子钙成像追踪活动模式 在此期间，为了了解海马区-皮质通讯的变化和 会导致癫痫的发展。所有的研究都是独立的，但作为一个多学科的研究，它们之间相互启发 对次元的理解将是在这种高度复杂和致残的障碍中取得进展的关键。

Temporal lobe epilepsy (TLE) is the most common form of epilepsy in adults and a major source of disability in the veteran population as it is frequently caused by war-time head injuries. More than 1/3 of TLE patients do not respond to anticonvulsant medications and many are not candidates for epilepsy surgery. Therefore, new treatments are needed to prevent the development of epilepsy after the initial insult. Yet, the mechanisms that lead to the development of epilepsy during the period directly after status epilepticus (SE) are still poorly understood. A deep and precise understanding of these mechanisms is critical for development of interventions that can treat temporal epilepsy without the side-effects of medications and potential disability from large surgical resections. To determine the network dynamic changes in specific cell types during the earliest period after SE, we have developed a miniaturized microscope that is completely integrated with a high channel extracellular electrophysiology recording device (E-Scope). We hypothesize that hypersynchronous firing of parvalbumin positive (PV+) and progressive decreased engagement of somatostatin+ (SOM+) interneurons emerge during the epileptogenic period after the insult. We also hypothesize that these pathological circuit dynamics in both excitatory and inhibitory neurons will be readily observed during 200-400 Hz high frequency oscillations (HFOs) have been shown to be a biomarker for hyper-excitable epileptic circuit. In Aim 1 we will measure how PV+ and SOM+ neurons become activated during pathological fast ripples and physiological sharp-wave ripples through the epileptogenic period. In Aim 2, we will measure the precision of spatial coding by excitatory neurons and the reactivation of ensembles during physiological sharp-wave ripples and pathological fast ripples through the epileptogenic period. This information will be critical for identifying the cell specific targets for interventions to prevent epileptogenesis. Overall Strategy: The overall goal of our collaborative merit proposal is to determine the key changes in hippocampal and neocortical circuitry that promotes the development of epilepsy and cognitive dysfunction after the initial insult. Aims of Other Proposals: 1. Wasterlain will use immunocytochemical techniques, including EM immunocytochemistry, to quantify changes in the GABA receptor expression at the synapse and in the peri-synaptic space. 2. Naylor will use in-vitro slice patch clamp recordings, optogenetics, and computational modeling to understand how the functional connectivity of different interneuron types changes during this key period. 3. Smirnakis will use a combination of electrophysiological techniques and in-vivo mesoscopic two-photon calcium imaging to track the activity patterns of neocortical neurons during this period, to understand how hippocampal-cortical communication changes and drives the development of epilepsy. All studies are independent, yet deeply inform each other, as a multi- dimensional understanding will be key for making progress in this highly complex and disabling disorder.