MECHANISMS OF SEIZURE-INDUCED DENDRITIC INJURY

描述(申请人提供)：癫痫患者通常会出现认知障碍，如记忆问题、学习障碍和智力低下。虽然环境和心理社会因素也可以影响大脑功能，但人们越来越关注癫痫发作本身在损害大脑方面的作用，从而导致癫痫患者进一步的神经功能障碍和下降，以及逐渐恶化的癫痫发作。癫痫发作可能通过各种机制损害大脑，包括神经元死亡。然而，由于许多癫痫患者在脑成像或病理研究中没有明显的神经元死亡的结构证据，癫痫发作对突触和树突-神经元沟通的关键部位-的结构和功能的“非致命性”影响，可能在导致癫痫患者大脑功能障碍方面同样重要。在我们之前的工作中，我们的实验室利用尖端成像技术在活体小鼠身上直接显示了癫痫发作对树突状细胞的损伤。在这个项目中，我们提出了一种假设，即一种特定的细胞信号通路，称为哺乳动物雷帕霉素靶点(MTOR)通路，参与了导致癫痫发作诱导的树突状细胞损伤。首先，我们将使用体内多光子成像技术来可视化抑制mTOR途径是否可以预防癫痫诱导的树突状细胞损伤。接下来，我们将通过调节其他细胞通路和与树突的肌动蛋白细胞骨架相关的分子来确定mTOR通路是否对树突具有神经保护作用。最后，我们将研究癫痫诱导的树突状细胞损伤与小鼠皮层感觉信息处理相关的生理和功能后果，并测试mTOR抑制剂维持正常功能的能力。这一项目应有助于深入了解癫痫发作对树突的有害影响 可能最终导致预防认知缺陷和癫痫的其他神经后果的新的治疗方法。

DESCRIPTION (provided by applicant): Epilepsy patients often experience cognitive deficits, such as memory problems, learning disabilities, and mental retardation. Although environmental and psychosocial factors can also affect brain function, there has been increasing focus on the role of seizures themselves in damaging the brain and thus causing further neurological deficits and decline in epilepsy patients, as well as progressively worsening seizures. Seizures can potentially injure the brain by a variety of mechanisms, including the death of neurons. However, since many people with epilepsy do not have obvious structural evidence of neuronal death on brain imaging or pathological studies, "non-lethal" effects of seizures on the structure and function of synapses and dendrites, the critical sites where neurons communicate, may be equally important in causing brain dysfunction in epilepsy patients. In our previous work, our lab has utilized cutting-edge imaging techniques to directly visualize in living mice injury to dendrits caused by seizures. In this project, we propose to address the hypothesis that a specific cell signaling pathway, called the mammalian target of rapamycin (mTOR) pathway, is involved in causing seizure-induced dendritic injury. First, we will use in vivo multiphoton imaging techniques to visualize whether inhibiting the mTOR pathway can prevent seizure-induced dendritic injury. Next, we will determine whether the mTOR pathway has neuroprotective effects on dendrites by regulating other cellular pathways and molecules related to the actin cytoskeleton of dendrites. Finally, we will investigate the physiological and functional consequences of seizure-induced dendritic injury related to cortical processing of sensory information in mice and test the ability of mTOR inhibitors to preserve normal function. This project should lead to important insights into the detrimental effects of seizures on dendrites and may ultimately lead to novel therapeutic approaches for preventing cognitive deficits and other neurological consequences of epilepsy.