Activity-dependent endocannabinoid control in epilepsy

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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.