Activity-dependent endocannabinoid control in epilepsy

颞叶癫痫(TLE)是成人最常见的癫痫综合征。当前的治疗方案 对于TLE来说，由于许多患者癫痫发作失控和消极治疗，TLE往往仍然不够 副作用。涉及大麻素1型受体(CB1)的内源性大麻素信号转导 被认为是突触前抑制神经递质GABA释放的主要调节器 中枢神经系统。然而，尽管内源性和外源性大麻素的治疗潜力一直是 公认为各种神经和精神疾病，大麻素的体内机制 信号转导仍然知之甚少，限制了新疗法的有效设计。我们的主要原因是 对完整大脑中的大麻素信号的不完全理解包括高度不稳定的性质 脂源性大麻素配体和以往缺乏研究CB1表达神经元行为的方法 动物。最近，我们推出了克服这些挑战的新工具，最终提供了 研究人员既有能力检测行为正常的小鼠海马体中的快速脂肪信号，也有能力 选择性地监测和操纵体内表达CB1的GABA能细胞。在这里，我们建议使用 这些新工具用于检验假设，即活动依赖的内源性大麻素在完整的 慢性TLE患者海马区持续改变。然后，我们将利用新颖、非侵入性、封闭式- 以CB1表达的GABA能细胞为靶点的环状干预，以控制慢性癫痫发作和 改善空间信息处理中与TLE相关的干扰。我们将在下面测试我们的假设 慢性TLE的实验性小鼠模型，利用各种创新的体内钙成像， 电生理学、光遗传学和行为学方法。我们预计我们的项目将会有 通过克服有关依赖活动的主要知识差距，产生重大的、潜在的可翻译影响 行为动物正常和癫痫神经元回路中的大麻素信号，并通过加速 开发非侵入性闭环干预策略。

Temporal lobe epilepsy (TLE) is the most common epilepsy syndrome in adults. Current treatment options for TLE remain often inadequate, as many patients suffer from uncontrolled seizures and negative treatment side effects. Endogenous cannabinoid signaling involving the cannabinoid type 1 receptor (CB1) is recognized to be a major presynaptic regulator of inhibitory neurotransmitter GABA release throughout the CNS. However, although the therapeutic potential of endo- and exogenous cannabinoids has been recognized for various neurological and psychiatric disorders, the in vivo mechanisms of cannabinoid signaling remain poorly understood, limiting the effective design of novel therapies. Major reasons for our incomplete understanding of cannabinoid signaling in the intact brain include the highly unstable nature of lipid-derived cannabinoid ligands and the prior lack of methods to study CB1-expressing neurons in behaving animals. Recently, we have introduced new tools that overcome these challenges, finally offering researchers both the ability to detect fast lipid signals in the hippocampus of behaving mice, and to selectively monitor and manipulate CB1-expressing GABAergic cells in vivo. Here, we propose to employ these new tools to test the hypothesis that activity-dependent endocannabinoid dynamics in the intact hippocampus are persistently modified in chronic TLE. We will then leverage novel, non-invasive, closed- loop interventions to target CB1-expressing GABAergic cells in order to control chronic seizures and ameliorate TLE-related disturbances in spatial information processing. We will test our hypothesis in experimental mouse models of chronic TLE, utilizing a variety of innovative in vivo calcium-imaging, electrophysiology, optogenetic and behavioral approaches. We anticipate that our project will have significant, potentially translatable, impact by overcoming major knowledge gaps about activity-dependent cannabinoid signaling in normal and epileptic neuronal circuits in behaving animals, and by accelerating the development of non-invasive closed-loop intervention strategies.