Activity-dependent endocannabinoid control in epilepsy

颞叶癫痫（TLE）是成人最常见的癫痫综合征。当前治疗选择 对于TLE仍然往往不足，因为许多患者患有不受控制的癫痫发作和消极治疗， 副作用.涉及大麻素1型受体（CB 1）的内源性大麻素信号传导是 被认为是抑制性神经递质GABA释放的主要突触前调节剂， CNS。然而，尽管内源性和外源性大麻素的治疗潜力已经被证实， 大麻素被公认为各种神经和精神疾病， 信号传导仍然知之甚少，限制了新疗法的有效设计。我们的主要原因 对完整大脑中大麻素信号传导的不完全理解包括 脂质衍生的大麻素配体和先前缺乏研究CB 1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， 研究人员发现，在行为正常的小鼠海马体中检测快速脂质信号的能力， 选择性地监测和操纵体内表达CB 1的GABA能细胞。在这里，我们建议雇用 这些新的工具来测试这一假设，即活动依赖性内源性大麻素动力学在完整的 海马在慢性TLE中持续改变。我们将利用新颖的，非侵入性的，封闭的- 回路干预靶向CB 1表达GABA能细胞，以控制慢性癫痫发作， 改善空间信息处理中的TLE相关干扰。我们将测试我们的假设， 慢性TLE的实验小鼠模型，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，我们的项目将有 通过克服关于依赖活动的 大麻素信号在正常和癫痫神经元回路的行为动物，并通过加速 制定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.