STATUS EPILEPTICUS REORGANIZES CANNABINOID RECEPTORS

中枢神经系统大麻素受体 (CB1) 是最丰富的 G 蛋白偶联受体之一 大脑中的受体并介导大麻素物质对神经元功能的许多影响。我们的 实验室证明，毛果芸香碱持续一小时的癫痫发作（癫痫持续状态，SE） SE 模型对 CB1 受体的表达产生长期重组，这些 CB1表达的变化基本上在动物的一生中持续存在。 SE是一个主要的神经系统疾病 死亡率和发病率较高的紧急情况，包括获得性癫痫 (AE) 和记忆缺陷。 我们的初步结果表明，SE 诱导了表达和功能的持续变化。 CB1受体被重组，抑制性神经末梢减少，兴奋性神经末梢增加， 表明这种长期可塑性变化可能代表神经元功能的重要调节剂。 这项研究工作将测试中心假设，即 SE（急性事件）会导致长期持续的重组 CB1 的表达导致内源性大麻素整体功能的持续变化 系统，对谷氨酸释放产生更大的抑制，对 GABA 释放的抑制更小 与控制大脑相比，癫痫发作并最终导致动物行为的变化，如 记忆缺陷。为了检验这一假设，我们将实现以下具体目标： 目标 1. 评估是否 单独的 SE 或与 AE 一起发生会导致免疫反应性的持续重排， 大脑中 CB1 受体的表达并评估这些变化的时间进程；目标 2. 确定是否 SE 诱导的 CB1 受体表达变化与 CB1 的相应变化相关 由 G 蛋白激活、受体结合和神经递质释放调节决定的功能； 目标 3. 确定 SE 诱导的 CB1 受体重组与兴奋性和抑制性的关联 神经末梢；目标 4. 确定长期可塑性变化对 CB1 表达和功能的影响 SE 后观察到的长期记忆效应。这项研究的目的是确定是否发生变化 SE 后 CB1 系统的表达导致神经元兴奋性改变和记忆缺陷 由SE生产。这些研究可能会导致新的治疗干预措施的开发，以逆转 SE 通过药理调节内源 CB1 系统对 AE 和记忆丧失产生影响。

The central nervous system cannabinoid receptor (CB1) is one of the most abundant G-Protein coupled receptors in brain and mediates many of the effects of cannabinoid substances on neuronal function. Our laboratory has demonstrated that one hour of prolonged seizures (status epilepticus, SE) in the pilocarpine model of SE produces a long-term reorganization in the expression of the CB1 receptor ahd that these changes in CB1 expression persist for essentially the life of the animal. SE is a major neurological emergency that has a high mortality and morbidity, including acquired epilepsy (AE) and memory deficits. Our preliminary results suggest that the SE induced persistent changes in expression and function of the CB1 receptor are reorganized to be decreased on inhibitory and increased on excitatory nerve terminals, indicating that this long-term plasticity change may represent a significant modulator of neuronal function. This research effort will test the Central Hypothesis that SE (acute event) causes long lasting reorganization in the expression of the CB1 that results in persistent changes in the overall function of the endocannabinoid system, causing a greater inhibition of glutamate release and a smaller inhibition of GABA release in epileptic compared to control brain and ultimately in changes in the behavior of the animal, as manifested by memory deficits. To test this hypothesis we will conduct the following specific aims: Aim 1. Evaluate whether SE alone or with the development of AE causes persistent rearrangements in the immunoreactivity and expression of the CB1 receptor in brain and evaluate the time course of these changes; Aim 2. Determine if the SE induced changes in CB1 receptor expression are associated with corresponding changes in CB1 function as determined by G-protein activation, receptor binding and regulation of neurotransmiter release; Aim 3. Determine the association of SE induced CB1 receptor reorganization on excitatory and inhibitory nerve terminals; Aim 4. Determine the effects of long-term plasticity changes in CB1 expression and function on the long-term memory effects observed after SE. The goal of this research is to determine if changes in the expression of the CB1 system following SE contribute to altered neuronal excitability and memory deficits produced by SE. These studies may lead to the development of novel therapeutic interventions to reverse the effects of SE on AE and memory loss by pharmacologically regulating the endogenous CB1system.