STATUS EPILEPTICUS REORGANIZES CANNABINOID RECEPTORS

描述（由申请人提供）：中枢神经系统大麻素受体（CB 1）是大脑中最丰富的G蛋白偶联受体之一，介导大麻素物质对神经元功能的许多作用。我们的实验室已经证明，在SE的匹鲁卡品模型中，一小时的长时间癫痫发作（癫痫持续状态，SE）产生CB 1受体表达的长期重组，并且这些CB 1表达的变化基本上持续动物的生命。SE是一种主要的神经系统急症，具有高死亡率和发病率，包括获得性癫痫（AE）和记忆缺陷。我们的初步研究结果表明，SE诱导的持续变化的表达和功能的CB 1受体的重组减少抑制性和兴奋性神经末梢增加，表明这种长期的可塑性变化可能是一个显着的调制器的神经元功能。这项研究工作将测试中心假说，即SE（急性事件）导致CB 1表达的长期重组，导致内源性大麻素系统整体功能的持续变化，导致与对照大脑相比，癫痫患者对谷氨酸释放的抑制更大，对GABA释放的抑制更小，最终导致动物行为的变化，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。评价SE单独或与AE的发展是否导致脑中CB 1受体的免疫反应性和表达的持续重排，并评价这些变化的时间过程;目的2。确定SE诱导的CB 1受体表达的变化是否与CB 1功能的相应变化相关，如通过G蛋白活化、受体结合和神经递质释放的调节所确定的;目的3。确定SE诱导的兴奋性和抑制性神经末梢上CB 1受体重组的关联;目的4.确定CB 1表达和功能的长期可塑性变化对SE后观察到的长期记忆效应的影响。本研究的目的是确定SE后CB 1系统表达的变化是否有助于改变SE产生的神经元兴奋性和记忆缺陷。这些研究可能会导致开发新的治疗干预措施，以逆转SE对AE和记忆丧失的影响，通过调节内源性CB 1系统。

DESCRIPTION (provided by applicant): 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 CB1 system.