title: Crucial Roles of the Endocannabinoid 2-Arachidonoylglycerol in the Suppression of Epileptic Seizures.
abstract: Endocannabinoid signaling is considered to suppress excessive excitability of neural circuits and to protect the brain from seizures. However, the precise mechanisms of this effect are poorly understood. Here, we report that 2-arachidonoylglycerol (2-AG), one of the two major endocannabinoids, is crucial for suppressing seizures. We found that kainate-induced seizures in mice lacking the 2-AG synthesizing enzyme, diacylglycerol lipase α, were much more severe compared with those in cannabinoid CB1 receptor knockout mice and were comparable to those in mice lacking both CB1- and CB2-receptor-mediated signaling. In the dentate gyrus, 2-AG suppressed excitatory input around the inner and middle molecular layers through CB1 and presumably CB2 receptors, respectively. This 2-AG-mediated suppression contributed to decreased granule cell excitability and the dampening of seizures. Furthermore, lack of 2-AG signaling enhanced kindling epileptogenesis and spontaneous seizures after kainate-induced status epilepticus. These results highlight critical roles of 2-AG signaling in the suppression of epileptic seizures.
authors.affiliation: Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Sugaya
authors.affiliation: Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
authors.forename: Maya
authors.initials: M
authors.lastname: Yamazaki
authors.affiliation: Department of Anatomy and Embryology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors.forename: Motokazu
authors.initials: M
authors.lastname: Uchigashima
authors.affiliation: Section of Viral Vector Development, National Institute for Physiological Sciences, Okazaki 444-8585, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Anatomy and Embryology, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Cellular Neurobiology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakimura
authors.affiliation: Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan. Electronic address: mkano-tky@m.u-tokyo.ac.jp.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kano
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D018891:Dentate Gyrus / Q000378:metabolism; D063388:Endocannabinoids / Q000378:metabolism*; D005260:Female; D005989:Glycerides / Q000378:metabolism*; D008071:Lipoprotein Lipase / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D012640:Seizures / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013569:Synapses / Q000378:metabolism
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C094503:glyceryl 2-arachidonate; D008071:Lipoprotein Lipase