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: 10448411
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10448411
• 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; Hyperactivity; Hypothalamic structure; Impairment; Knock-in Mouse; Label; Lead; Medial; Microscopic; Modeling; Neurons; Patients; Persons; Research Personnel; Resistance; Seizures; Sleep; Somatosensory Cortex; Structure; Synapses; Transgenic Mice; acquired epilepsy; 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.

在美国，癫痫发作影响着300多万人，给患者和他们的家人带来了巨大的负担