title: The endocannabinoid system controls key epileptogenic circuits in the hippocampus.
abstract: Balanced control of neuronal activity is central in maintaining function and viability of neuronal circuits. The endocannabinoid system tightly controls neuronal excitability. Here, we show that endocannabinoids directly target hippocampal glutamatergic neurons to provide protection against acute epileptiform seizures in mice. Functional CB1 cannabinoid receptors are present on glutamatergic terminals of the hippocampal formation, colocalizing with vesicular glutamate transporter 1 (VGluT1). Conditional deletion of the CB1 gene either in cortical glutamatergic neurons or in forebrain GABAergic neurons, as well as virally induced deletion of the CB1 gene in the hippocampus, demonstrate that the presence of CB1 receptors in glutamatergic hippocampal neurons is both necessary and sufficient to provide substantial endogenous protection against kainic acid (KA)-induced seizures. The direct endocannabinoid-mediated control of hippocampal glutamatergic neurotransmission may constitute a promising therapeutic target for the treatment of disorders associated with excessive excitatory neuronal activity.
authors.affiliation: Department of Physiological Chemistry, Johannes Gutenberg University, Duesbergweg 6, 55099 Mainz, Germany.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Monory
authors.forename: Federico
authors.initials: F
authors.lastname: Massa
authors.forename: Michaela
authors.initials: M
authors.lastname: Egertová
authors.forename: Matthias
authors.initials: M
authors.lastname: Eder
authors.forename: Heike
authors.initials: H
authors.lastname: Blaudzun
authors.forename: Ruth
authors.initials: R
authors.lastname: Westenbroek
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kelsch
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jacob
authors.forename: Rudolf
authors.initials: R
authors.lastname: Marsch
authors.forename: Marc
authors.initials: M
authors.lastname: Ekker
authors.forename: Jason
authors.initials: J
authors.lastname: Long
authors.forename: John L
authors.initials: JL
authors.lastname: Rubenstein
authors.forename: Sandra
authors.initials: S
authors.lastname: Goebbels
authors.forename: Klaus-Armin
authors.initials: KA
authors.lastname: Nave
authors.forename: Matthew
authors.initials: M
authors.lastname: During
authors.forename: Matthias
authors.initials: M
authors.lastname: Klugmann
authors.forename: Barbara
authors.initials: B
authors.lastname: Wölfel
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Dodt
authors.forename: Walter
authors.initials: W
authors.lastname: Zieglgänsberger
authors.forename: Carsten T
authors.initials: CT
authors.lastname: Wotjak
authors.forename: Ken
authors.initials: K
authors.lastname: Mackie
authors.forename: Maurice R
authors.initials: MR
authors.lastname: Elphick
authors.forename: Giovanni
authors.initials: G
authors.lastname: Marsicano
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D048588:Benzoxazines; D002121:Calcium Channel Blockers / Q000494:pharmacology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D063388:Endocannabinoids; D004827:Epilepsy / Q000139:chemically induced / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D015870:Gene Expression / Q000502:physiology; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009415:Nerve Net / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D017966:Pyramidal Cells / Q000502:physiology / Q000528:radiation effects; D043884:Receptor, Cannabinoid, CB1 / Q000172:deficiency; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000235:genetics
chemical_list: D048588:Benzoxazines; D002121:Calcium Channel Blockers; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D009025:Morpholines; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; C493465:Slc17a7 protein, mouse; D050598:Vesicular Glutamate Transport Protein 1; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D007608:Kainic Acid