Subcortical nodes within epileptic network control the cortical disfacilitation to prompt seizure onset in IGE mouse model

癫痫发作影响美国300多万人，给患者和他们的 家庭/社区。一些有遗传原因的顽固性癫痫发作(特发性全身性癫痫，IGE)是 对常规抗癫痫药物产生抗药性。尽管在机制方面取得了重大进展 在获得性癫痫中，免疫球蛋白E的病因仍然难以捉摸。我们还没有完全理解平衡是如何 在免疫球蛋白E的某些条件下，突触/神经元的兴奋和抑制之间的动态损伤 模特们。此外，不可否认的是，癫痫发作的功能磁共振研究表明，全脑网络(皮质 和远程皮质下结节)参与癫痫活动，表明癫痫发作是新出现的 全脑癫痫网络活动在微观、中观和宏观上的后果 比例。然而，对于临床研究人员来说，预测癫痫网络节点如何变化仍然具有挑战性。 在网络水平上相互作用，在癫痫发作期间产生高压尖峰波放电(SWD)。 具体地说，以前没有任何研究关注IGE中癫痫发作和癫痫活动的确切原因。 癫痫模型是通过癫痫网络节点之间的相互作用在网络层面启动的，为什么癫痫发作 在人类癫痫患者中，大多数发生在睡眠-觉醒转换/安静-清醒时期，为什么癫痫发作- 预兆条件，如情绪先兆先兆现象，可导致后天两者癫痫发作 癫痫和IGE患者。因此，我们假设癫痫网络节点内的皮质下节点， 特别是下丘脑前核和杏仁内侧核，控制皮质障碍(神经元 由于缺乏兴奋性突触活动而导致的超极化(Contrera等人，1996；TimoFeev等人，1996； 2001)，在睡眠-觉醒转换/安静-觉醒时期和其他情绪先兆光环。由此产生的 皮质障碍促使高压慢波振荡(SWO)，从而增强止血作用 皮层中癫痫神经元的突触兴奋(而不是抑制)。最终，这些链条 事件导致癫痫网络内皮质神经元的同步放电，从而触发癫痫发作和SWDS。它 是我们的免疫球蛋白E小鼠模型中先前的皮质障碍状态(存在于睡眠-觉醒期间 过渡/安静-觉醒时期和一些情绪先兆先兆状态)，从而控制癫痫发作 发病和癫痫活动，为免疫球蛋白E模型提供了网络机制。这项提案将使用 表达神经元GFP的转基因小鼠(由活性依赖的c-Fos启动子驱动)鉴定 杂合子Gabrg2Q390X或Gabra1A322D在皮质和皮质下结构中的癫痫网络结节 并确定下丘脑前部和杏仁内侧是否会引起皮质 这些Ki小鼠体内光遗传刺激的障碍(表达ChR2/卤视紫质的神经元 C-Fos启动子驱动)，最终在大脑皮层和大脑皮层诱发SWO并引发癫痫SWD 导致癫痫发作。提出了治疗IGE的新药，作为原理研究的证据。

Seizures affect more than 3 million people in US, creating tremendous burdens to patients and their families/communities. Some intractable seizures with genetic causes (idiopathic generalized epilepsy, IGE) are resistant to conventional antiepileptic drugs. Although major progress has been made regarding mechanisms of acquired epilepsy, the causes for IGE remain elusive. We have not completely understood how the balance between synaptic/neuron excitation and inhibition is dynamically impaired under some conditions for IGE models. Moreover, functional MRI studies on seizures undeniably indicate that whole-brain networks (cortical and remote subcortical nodes) are involved during epileptic activity, suggesting that seizures are the emerging consequence of whole-brain epileptic network activity at the microscopic, mesoscopic, and macroscopic scales. However, it still remains challenging for clinical researchers to forecast how epileptic network nodes interact at network levels to generate the high-voltage spike-wave discharges (SWDs) during seizures. Specifically, no previous studies have ever focused on exactly how seizure onset and epileptic activity in IGE models are initiated through the interaction between epileptic network nodes at the network level, why seizures in human epileptic patients mostly occur during sleep-wake transition/quiet-awake period, and why seizure- presage conditions such as emotional prodromic aura phenomena can cause seizures in both acquired epilepsy and IGE patients. Thus, we hypothesize that subcortical nodes within epileptic network nodes, specifically anterior hypothalamus nucleus and medial amygdala, control cortical disfacilitation (neurons are hyperpolarized due to the absence of excitatory synaptic activity(Contreras et al., 1996; Timofeev et al., 1996; 2001)) during sleep-wake transition/quiet-awake period and other emotional prodromic auras. The resulting cortical disfacilitation prompts high-voltage slow-wave oscillations (SWOs), which hemostatically potentiate synaptic excitation (not inhibition) of epileptic neuron ensembles/engrams in the cortex. Eventually, these chain events lead to cortical neuron synchronous firing within epileptic network to trigger seizure onset and SWDs. It is the preceding cortical disfacilitation state in our IGE mouse models (present during sleep-wake transition/quiet-awake period and some emotion prodromic aura states) that consequently controls seizure onset and epileptic activity, which offers the network mechanism for IGE models. This proposal will use transgenic mice with neuron GFP expression (driven by activity dependent c-Fos promoter) to identify the epileptic network nodes in both cortex and subcortical structures in heterozygous Gabrg2Q390X or Gabra1A322D KI mice and determine whether the anterior hypothalamus and medial amygdala can cause cortical disfacilitation with optogenetic stimulation in vivo in these KI mice(neuron expressing ChR2/halorhodopsin driven by c-Fos promoter), which eventually induces SWOs and instigates epileptic SWDs in the cortex and generate seizures. New drugs for IGE treatment are proposed for a proof of principle study.