The mitochondrial Ca2+ uniporter in the regulation of neural activity and susceptibility to seizures

线粒体 Ca2 单向转运蛋白在神经活动和癫痫易感性调节中的作用

• 批准号: 10392188
• 负责人: Yuriy M Usachev
• 金额: $ 44.92万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-15 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10392188
• 关键词: Affect; Anticonvulsants; Behavioral; Bioenergetics; Cause of Death; Cell Death; Chronic; Cognitive deficits; Complex; Data; Development; Electroconvulsive Shock; Electrophysiology (science); Epilepsy; Fluorescent Probes; Foundations; Future; Generations; Genetic Engineering; Glutamates; Hippocampus (Brain); Impaired cognition; In Vitro; Inner mitochondrial membrane; Intervention; Intractable Epilepsy; Knock-out; Knockout Mice; Lead; Light; Mitochondria; Modeling; Morbidity - disease rate; Mus; Neurons; Patients; Persons; Pharmacologic Substance; Pilocarpine; Pilot Projects; Play; Predisposition; Process; Property; Regulation; Role; Seizures; Sensory; Signal Transduction; Slice; Synapses; Synaptic Transmission; Temporal Lobe Epilepsy; Testing; Toxic effect; Translational Research; Work; behavior test; calmodulin-dependent protein kinase II; excitatory neuron; excitotoxicity; high risk; in vivo; insight; mortality; motor deficit; mouse model; nervous system disorder; neural network; neuron loss; neuronal excitability; neuroregulation; neurotoxicity; novel; optogenetics; patch clamp; patient population; presynaptic; prevent; psychiatric comorbidity; relating to nervous system; sudden unexpected death in epilepsy; synaptic function; therapeutic target; transmission process; uptake

Project Summary/Abstract Epilepsy is a common neurological disorder that affects approximately 70 mln people. For many patients, epilepsy can be controlled through pharmaceutical therapies; however, approximately 30% of patients develop refractory epilepsy that cannot be controlled with current pharmaceutical interventions. Refractory epilepsy is associated with a high risk for sudden unexpected death in epilepsy (SUDEP), which is the leading cause of death in this patient population. In addition, uncontrolled epilepsy and frequent seizures are associated with progressive cognitive decline, as well as significant behavioral and psychiatric comorbidities. Thus, it is of paramount importance to identify novel critical therapeutic targets for patients with refractory epilepsy. The main objective of this proposal is to establish the role of the mitochondrial Ca2+ uniporter (MCU) in regulating synaptic function, neural network activity and seizure susceptibility. MCU is the core component of the mitochondrial Ca2+ uptake complex and is involved in the regulation of Ca2+ signaling, bioenergetics and cell death. Our focus on MCU is inspired by several novel observations we made during our pilot studies. First, we found that MCU knockout (KO) produces robust anticonvulsant effects both in vivo and in vitro. Second, deleting MCU specifically in GABAergic, but not in glutamatergic, neurons was sufficient to produce an anticonvulsant effect. Third, MCU deletion enhanced GABAergic synaptic transmission, but did not alter glutamatergic transmission or intrinsic neuronal excitability. Fourth, MCU deletion protected neurons from glutamate-induced Ca2+ deregulation and toxicity. The latter is important because excitotoxicity contributes significantly to neuronal damage in epilepsy. Collectively, these data suggest that inhibiting MCU would provide a dual benefit in the context of epilepsy, first by increasing seizure threshold, and second, by protecting neurons from excitotoxicity associated with seizures. We hypothesize that MCU plays an important role in regulating GABAergic synaptic transmission and neural activity, and that MCU deletion produces anticonvulsant effects by enhancing GABAergic synaptic transmission and preventing neural network hyperexcitability. We also hypothesize that MCU deletion provides protection from neurotoxicity associated with seizures. These central hypotheses will be tested in 3 specific aims. Aim 1 will establish the roles of GABAergic and glutamatergic neurons in the anticonvulsant effect of MCU deletion. Aim 2 will determine the role of MCU at inhibitory and excitatory central synapses. Aim 3 will determine the role of MCU in epilepsy-induced neuronal toxicity. The proposed studies will provide mechanistic insight into a previously unrecognized role of mitochondrial Ca2+ transport in regulating the activities of synaptic networks and susceptibility to hyperexcitability and seizures, and could lead to development of new strategies targeting mitochondrial Ca2+ transport and MCU for the treatment of epilepsy as well as other neurological disorders associated with aberrant neural activity.

项目摘要/摘要 癫痫是一种常见的神经系统疾病，影响约70万人。对于许多患者， 癫痫可以通过药物疗法控制；但是，大约30％的患者发展 无法通过当前药物干预措施控制的难治性癫痫。难治性癫痫是 与癫痫（SUDEP）突然出现意外死亡的高风险有关，这是 该患者人群的死亡。另外，不受控制的癫痫和频繁癫痫发作与 渐进的认知能力下降以及重大的行为和精神病合并症。因此，它是 对于难治性癫痫患者的新型关键治疗靶标，至关重要。主 该建议的目的是确定线粒体Ca2+ Uniporter（MCU）在调节突触中的作用 功能，神经网络活动和癫痫发作敏感性。 MCU是线粒体Ca2+的核心组成部分 吸收复合物，并参与了CA2+信号传导，生物能和细胞死亡的调节。我们专注于 MCU的灵感来自我们在试点研究中进行的一些新颖观察结果。首先，我们发现MCU 敲除（KO）在体内和体外产生强大的抗惊厥作用。第二，专门删除MCU 在Gabaergic中，但在谷氨酸能及其中不足，神经元足以产生抗惊厥作用。第三，MCU 删除增强的GABA能突触传播，但没有改变谷氨酸能传播或固有 神经元兴奋性。第四，MCU缺失保护神经元免受谷氨酸诱导的Ca2+放松调节和 毒性。后者很重要，因为兴奋性毒性对癫痫的神经元损伤产生了重要贡献。 总的来说，这些数据表明，抑制MCU将在癫痫的背景下提供双重好处，首先 通过保护神经元免受与癫痫发作相关的兴奋性毒性，通过增加癫痫发作阈值，其次。 我们假设MCU在调节GABA能突触传播和神经方面起着重要作用 活动，MCU缺失通过增强GABA能传播产生抗惊厥作用 并防止神经网络过度兴奋。我们还假设MCU删除提供了保护 来自与癫痫发作相关的神经毒性。这些中心假设将以3个特定目标进行测试。目标1 将确定GABA能和谷氨酸能神经元在MCU缺失的抗惊厥作用中的作用。 AIM 2将确定MCU在抑制性和兴奋性中心突触中的作用。 AIM 3将决定角色 癫痫引起的神经元毒性中的MCU。拟议的研究将提供机械洞察 线粒体Ca2+转运在调节突触网络和 对过度兴奋和癫痫发作的敏感性，并可能导致针对目标的新策略 线粒体Ca2+运输和MCU用于治疗癫痫以及其他神经系统疾病 与异常的神经活动相关。