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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要癫痫是一种常见的神经系统疾病，影响着大约 7000 万人。对于很多患者来说，癫痫可以通过药物治疗得到控制；然而，大约 30% 的患者会出现目前的药物干预措施无法控制的难治性癫痫。难治性癫痫是与癫痫猝死（SUDEP）的高风险相关，这是癫痫的主要原因该患者群体中的死亡。此外，不受控制的癫痫和频繁的癫痫发作也与进行性认知能力下降，以及显着的行为和精神合并症。因此，它是为难治性癫痫患者确定新的关键治疗靶点至关重要。主要该提案的目的是确定线粒体 Ca2+ 单向转运蛋白 (MCU) 在调节突触中的作用功能、神经网络活动和癫痫易感性。 MCU是线粒体Ca2+的核心成分摄取复合物并参与 Ca2+ 信号传导、生物能学和细胞死亡的调节。我们的重点是 MCU 的灵感来自于我们在试点研究期间所做的一些新观察。首先，我们发现MCU 基因敲除（KO）在体内和体外均产生强大的抗惊厥作用。二、专门删除MCU 在 GABA 能神经元中（但在谷氨酸能神经元中则不然）足以产生抗惊厥作用。三、单片机缺失增强了 GABA 能突触传递，但没有改变谷氨酸能传递或内在的神经元的兴奋性。第四，MCU 缺失保护神经元免受谷氨酸诱导的 Ca2+ 失调和毒性。后者很重要，因为兴奋性毒性对癫痫的神经元损伤有显着影响。总的来说，这些数据表明，抑制 MCU 对癫痫有双重益处，首先首先，通过增加癫痫阈值，其次，通过保护神经元免受与癫痫发作相关的兴奋性毒性。我们假设 MCU 在调节 GABA 能突触传递和神经元中发挥重要作用活性，并且 MCU 缺失通过增强 GABA 突触传递产生抗惊厥作用并防止神经网络过度兴奋。我们还假设 MCU 删除提供了保护与癫痫发作相关的神经毒性。这些中心假设将在 3 个具体目标中得到检验。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。目标 2 将确定 MCU 在抑制性和兴奋性中枢突触中的作用。目标 3 将确定角色 MCU 在癫痫引起的神经元毒性中的作用。拟议的研究将为机制提供见解以前未认识到线粒体 Ca2+ 转运在调节突触网络活动中的作用容易过度兴奋和癫痫发作，并可能导致针对目标制定新策略线粒体 Ca2+ 转运和 MCU 用于治疗癫痫和其他神经系统疾病与异常的神经活动有关。