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Activity-dependent endocannabinoid control in epilepsy

癫痫的活动依赖性内源性大麻素控制

基本信息

批准号：
10639147
负责人：
Attila Losonczy
金额：
$ 59.93万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10639147
关键词：
2-arachidonylglycerol 3-Dimensional Acceleration Address Adult Animals Axon Behavior Behavioral Biotechnology Brain CNR1 gene Calcium Cannabinoids Cannabis Cells Cephalic Chronic Data Development Electroencephalography Electrophysiology (science)Endocannabinoids Epilepsy Exhibits Focused Ultrasound G-Protein-Coupled Receptors Generations Hippocampus Hyperactivity Image Injections Intervention Knowledge Ligands Lipids Measures Mental disorders Methods Modality Modeling Monitor Mus Myoepithelial cell Nature Neurons Neurotransmitters Patients Pattern Persons Physiological Pilocarpine Presynaptic Terminals Process Pyramidal Cells Research Personnel Resistance Seizures Sensory Signal Transduction Specificity Syndrome Temporal Lobe Epilepsy Testing Therapeutic Transgenic Mice Treatment Efficacy Treatment Side Effects cell type complement C2a design endocannabinoid signaling exogenous cannabinoid gamma-Aminobutyric Acid in vivo in vivo calcium imaging information processing inhibitory neuron innovation interest kainate mouse model nervous system disorder neuronal cell body neuronal circuitry novel novel therapeutics optogenetics place fields postsynaptic presynaptic receptor sensor spatiotemporal tool two-photon

项目摘要

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.

颞叶癫痫（TLE）是成人最常见的癫痫综合征。目前的治疗方案