STATUS EPILEPTICUS REORGANIZES CANNABINOID RECEPTORS

中枢神经系统大麻素受体（CB 1）是最丰富的G蛋白偶联受体之一， 大麻素受体在大脑中起重要作用，并介导大麻素物质对神经元功能的许多影响。我们 实验室已经证明，一个小时的长时间癫痫发作（癫痫持续状态，SE），在毛果芸香碱 SE模型在CB 1受体的表达中产生长期重组， CB 1表达的变化基本上持续动物的一生。SE是一种主要的神经系统疾病， 急性癫痫是一种具有高死亡率和发病率的急症，包括获得性癫痫（AE）和记忆缺陷。 我们的初步结果表明，SE诱导的表达和功能的持续变化， CB 1受体重组后在抑制性神经末梢上减少，在兴奋性神经末梢上增加， 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）导致长期持续的重组 CB 1的表达导致内源性大麻素整体功能的持续变化 系统，引起谷氨酸释放的较大抑制和GABA释放的较小抑制， 癫痫相比，控制大脑，并最终在动物的行为变化，表现为 记忆缺陷为了验证这个假设，我们将进行以下具体目标：目标1。评估是否 SE单独或与AE的发展引起免疫反应性的持续重排， CB 1受体在脑中的表达，并评估这些变化的时间过程;目的2.确定是否 SE诱导的CB 1受体表达的变化与CB 1受体表达的相应变化相关。 通过G蛋白活化、受体结合和神经递质释放调节确定的功能; 目标3。确定SE诱导的CB 1受体重组对兴奋性和抑制性 神经末梢; Aim 4.确定CB 1表达和功能的长期可塑性变化的影响 对SE后观察到的长期记忆影响。这项研究的目的是确定， SE后CB 1系统的表达有助于改变神经元兴奋性和记忆缺陷 由SE生产。这些研究可能会导致新的治疗干预的发展，以扭转 SE通过调节内源性CB 1系统对AE和记忆减退的影响。

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.