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

癫痫网络内的皮质下节点控制皮质功能障碍，促进 IGE 小鼠模型癫痫发作

• 批准号: 9756481
• 负责人: Chengwen Zhou
• 金额: $ 34.56万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9756481
• 关键词: Affect; Amygdaloid structure; Anterior; Anterior Hypothalamus; Antiepileptic Agents; Auras; Brain; Cell Nucleus; Chemosensitization; Clinical; Communities; Disease; Electric Stimulation; Emotional; Emotions; Epilepsy; Equilibrium; Event; FOS gene; Family; Functional Magnetic Resonance Imaging; Gene Mutation; Generalized Epilepsy; Generations; Genetic; Halorhodopsins; Hemostatic Agents; Human; Hyperactive behavior; Hypothalamic structure; Impairment; Knock-in Mouse; Label; Lead; Medial; Microscopic; Modeling; Neurons; Patients; Research Personnel; Resistance; Seizures; Sleep; Somatosensory Cortex; Structure; Synapses; Transgenic Mice; awake; base; in vivo; mouse model; novel therapeutics; optogenetics; prevent; promoter; voltage

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.

癫痫发作影响了美国300多万人，给患者及其家属造成了巨大的负担。 家庭/社区。一些遗传原因引起的顽固性癫痫发作（特发性全身性癫痫，IGE）， 对常规抗癫痫药物有抵抗力。虽然在机制方面取得了重大进展， 在获得性癫痫中，IGE的原因仍然难以捉摸。我们还没有完全理解 在IGE的某些条件下，突触/神经元兴奋和抑制之间的联系动态受损 模型此外，对癫痫发作的功能性MRI研究合理地表明，全脑网络（皮层） 和远端皮质下节点）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、中观和宏观上的结果 鳞片然而，对于临床研究人员来说，预测癫痫网络节点如何 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）。 具体来说，以前的研究从来没有集中在确切地如何癫痫发作和癫痫活动在IGE 模型是通过癫痫网络节点之间的相互作用在网络层面上启动的，为什么癫痫发作 人类癫痫患者大多发生在睡眠-觉醒过渡期/安静-觉醒期，为什么癫痫发作- 先兆条件，如情绪前驱先兆现象，可导致癫痫发作，在两个后天 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， 特别是前下丘脑核和内侧杏仁核，控制皮质障碍（神经元是 由于缺乏兴奋性突触活动而超极化（Contreras等，1996年; Zurfeev等人，一九九六年; 2001））在睡眠-觉醒过渡期/安静-觉醒期和其他情绪性前驱先兆期间。所得 皮层失易化提示高电压慢波振荡（SWO），其止血增强 皮层中癫痫神经元集合/痕迹的突触兴奋（非抑制）。最终，这些链条 事件导致癫痫网络内的皮层神经元同步放电以触发癫痫发作和SWD。它 在我们的IGE小鼠模型中（在睡眠-觉醒期间存在）， 过渡期/安静-清醒期和某些情绪前驱先兆状态），从而控制癫痫发作 发作和癫痫活动，这为IGE模型提供了网络机制。该提案将使用 用神经元GFP表达的转基因小鼠（由活性依赖性c-Fos启动子驱动）来鉴定 杂合子Gabrg 2 Q390 X或Gabra 1A 322 D中皮质和皮质下结构的癫痫网络节点 KI小鼠，并确定下丘脑前部和内侧杏仁核是否可以引起皮质 在这些KI小鼠（表达ChR 2/盐视紫红质的神经元）中， 由c-Fos启动子驱动），其最终诱导SWO并在皮质中引发癫痫SWD， 引发癫痫IGE治疗的新药被提议用于原理研究的证明。