STATUS EPILEPTICUS REORGANIZES CANNABINOID RECEPTORS

描述(申请人提供)：中枢神经系统大麻素受体(CB1)是大脑中含量最丰富的G蛋白偶联受体之一，介导大麻素类物质对神经功能的许多影响。我们的实验室已经证明，在匹罗卡品癫痫持续发作(癫痫持续状态，SE)模型中，一小时的癫痫发作会导致CB1受体表达的长期重组，并且这些CB1表达的变化基本上会持续到动物的一生。SE是一种重要的神经系统急症，具有高死亡率和高发病率，包括获得性癫痫(AE)和记忆障碍。我们的初步结果表明，SE引起的CB1受体表达和功能的持续变化在兴奋性神经末梢上被重组为抑制性减少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神经元功能的重要调节器。这项研究工作将检验中央假说，即SE(急性事件)导致CB1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，导致癫痫患者与对照组大脑相比对谷氨酸释放的更大抑制和对GABA释放的较小抑制，并最终改变动物的行为，表现为记忆缺陷。为了验证这一假说，我们将进行以下特定目的：目的1.评估SE是否单独或伴随着AE的发展导致脑内CB1受体免疫反应和表达的持续性重排，并评估这些变化的时间进程；目的2.确定SE诱导的CB1受体表达的变化是否与相应的CB1功能变化有关，如G蛋白激活、受体结合和神经递质释放调节所确定的；目的3.确定SE诱导的CB1受体重组对兴奋性和抑制性神经末梢的关联；目的4.确定长期可塑性变化的CB1表达和功能对SE后长期记忆效应的影响。这项研究的目的是确定在SE后CB1系统表达的变化是否有助于SE引起的神经元兴奋性和记忆障碍的改变。这些研究可能导致开发新的治疗干预措施，通过药理学调节内源性CB1系统来逆转SE对AE和记忆丧失的影响。

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.