Motor cortex plasticity in temporal lobe epilepsy

颞叶癫痫的运动皮层可塑性

• 批准号: 10180351
• 负责人: Jaideep Kapur
• 金额: $ 51.17万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10180351
• 关键词: AMPA Receptors; Address; Animal Model; Animals; Area; Behavioral; Biochemical; Brain; Cause of Death; Cell Count; Data; Development; Electroencephalography; Electrophysiology (science); Epilepsy; Estrogen Receptors; Exhibits; Experimental Models; FDA approved; FOS gene; Fracture; Fright; Genetic Recombination; Glutamates; Hippocampus (Brain); Image; Immediate-Early Genes; Injury; Investigation; Knockout Mice; Lasers; Long-Term Potentiation; Maps; Mediating; Methods; Microscope; Modeling; Molecular; Monitor; Motor Cortex; Mus; Neocortex; Neurons; Patients; Pentylenetetrazole; Persons; Pharmaceutical Preparations; Population; Property; Prosencephalon; Proteins; Refractory; Reporter; Research; Risk; Risk Factors; Role; Seizures; Seminal; Slice; Soft Tissue Injuries; Stimulus; Structure; Synapses; Techniques; Temporal Lobe Epilepsy; Testing; Tonic - clonic seizures; conditional knockout; dentate gyrus; eighth grade; experimental study; hippocampal pyramidal neuron; insight; kainate; knockout animal; motor learning; neocortical; novel; patch clamp; promoter; response; skill acquisition; sudden unexpected death in epilepsy; therapeutic target; third grade; transmission process

Project summary Grand mal (great malady) seizures, now called generalized tonic clonic seizures (GTCS), are the most feared seizures because they can cause death and injury. Repeated GTCSs are the leading risk factor for sudden unexpected death in epilepsy (SUDEP), which is a leading cause of death in persons with epilepsy. GTCS also leads to fractures and soft tissue injuries. It is long known that the motor cortex generates these seizures and seizures modify the motor cortex. However, the cellular and molecular mechanisms of seizure-induced reorganization of the motor cortex have not been studied. Furthermore, it is not known whether a GTCS makes subsequent seizures more severe. We propose that GTCS enhance the excitability of a subset of motor cortex pyramidal neurons by enhancing AMPA receptor mediated excitation. We found that GluA1 subunit of the AMPA receptor was essential for expressing kindling-induced (grade 5) GTCS. We kindled mice lacking the GluA1 subunit of AMPA receptors and their wild-type (WT) littermates using traditional kindling methods. Whereas WT animals progressed to sustained convulsive GTCS (grade 4 & 5), but knockout animals neither attained nor sustained GTCS, despite repeated stimulation. Furthermore, two (WT) animals died following GTCS, while none of the KO animals died. In Aim 1, we propose to characterize the role of the GluA1 subunit of AMPA receptors in sustaining repeated GTCSs using a combination of conditional knockout mice and biochemical techniques in intrahippocampal kainate (IHK) and kindling models of TLE. Behavioral seizures also become more intense when fully kindled animals were stimulated. Much larger volume of the cortex was active during the 8th GTCS compared to the neocortical activation observed after the 3rd GTCS. Motor cortex cell counts revealed that many more neurons in the motor cortex expressed c-fos in response to the fifth GTCS compared to the first GTCS. In Aim 2 experiments, we propose to confirm and expand these findings. we will compare cortical circuit activity maps and behavioral seizures in response to the first or fifth GTCS in kindling and IHK TLE models. We compared the electrophysiological properties of motor cortex pyramidal neurons that expressed c-fos in response to GTCSs with those of surrounding neurons that did not express c-fos and found surprising differences. Motor cortex pyramidal neurons expressing c-fos were more excitable and demonstrated enhanced AMPA receptor-mediated excitatory post synaptic currents. In Aim 3, we propose to compare the excitability and excitatory transmission of layer 2/3 and layer 4/5 pyramidal neurons expressing c- fos in response to a grade 5 kindled seizure using patch clamp recordings. These studies open a novel area of epilepsy research, focusing on the effects of GTCS on the neocortex using a combination combine novel, state-of-the-art techniques.

项目摘要 Grand Mal（大疾病）癫痫发作，现在被称为广义的音是癫痫发作（GTC），是最恐惧的 癫痫发作是因为它们会导致死亡和伤害。重复的GTCS是突然的主要危险因素 癫痫病（SUDEP）意外死亡，这是癫痫患者死亡的主要原因。 GTC也是如此 导致裂缝和软组织损伤。众所周知，运动皮层会产生这些癫痫发作和 癫痫发作可修饰运动皮层。但是，癫痫发作的细胞和分子机制 尚未研究运动皮层的重组。此外，尚不知道GTC是否制作 随后的癫痫发作更为严重。我们建议GTC提高了运动皮质子集的兴奋性 通过增强AMPA受体介导的激发，锥体神经元。我们发现glua1亚基的 AMPA受体对于表达发射诱导的（5级）GTC至关重要。我们点燃了缺乏的老鼠 使用传统的点燃方法，AMPA受体及其野生型（WT）同窝仔的GLUA1亚基。 wt动物发展为持续的抽搐GTC（4级和5级），但淘汰动物也不是 尽管反复刺激，但仍获得了或持续的GTC。此外，有两只（wt）动物死亡 GTC，而没有KO动物死亡。在AIM 1中，我们建议表征GLUA1亚基的作用 使用条件敲除小鼠和 Hapocampal Kainate（IHK）的生化技术和TLE的点燃模型。行为癫痫发作 当刺激完全点燃动物时，也会变得更加激烈。皮层的数量要大得多 与第三GTC后观察到的新皮质激活相比，在第8个GTC中活跃。运动皮层 细胞计数表明，运动皮层中的更多神经元对第五GTC表示C-FOS 与第一个GTC相比。在AIM 2实验中，我们建议确认和扩展这些发现。我们将 比较皮质电路活性图和行为癫痫 和IHK TLE模型。我们比较了运动皮层锥体神经元的电生理特性 对GTCS的响应表达C-FO，该GTCS具有未表达C-FOS并发现的周围神经元的C-FOS 令人惊讶的差异。表达C-FO的运动皮层锥体神经元更加兴奋，并且 展示了增强的AMPA受体介导的突触电流的兴奋性兴奋性。在AIM 3中，我们建议 比较表达C-的2/3层和4/5层神经元的兴奋性和兴奋性传播 FOS使用贴片夹记录响应5级点燃癫痫发作。这些研究为 癫痫研究，重点介绍GTC对新皮质的影响，使用组合组合小说， 最先进的技术。