title: Presynaptic specificity of endocannabinoid signaling in the hippocampus.
abstract: Endocannabinoids are retrograde messengers released by neurons to modulate the strength of their synaptic inputs. Endocannabinoids are thought to mediate the suppression of GABA release that follows depolarization of a hippocampal CA1 pyramidal neuron-termed "depolarization-induced suppression of inhibition" (DSI). Here, we report that DSI is absent in mice which lack cannabinoid receptor-1 (CB1). Pharmacological and kinetic evidence suggests that CB1 activation inhibits presynaptic Ca2+ channels through direct G protein inhibition. Paired recordings show that endocannabinoids selectively inhibit a subclass of synapses distinguished by their fast kinetics and large unitary conductance. Furthermore, cannabinoid-sensitive inputs are unusual among central nervous system synapses in that they use N- but not P/Q-type Ca2+ channels for neurotransmitter release. These results indicate that endocannabinoids are highly selective, rapid modulators of hippocampal inhibition.
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, 94143, USA.
authors.forename: R I
authors.initials: RI
authors.lastname: Wilson
authors.forename: G
authors.initials: G
authors.lastname: Kunos
authors.forename: R A
authors.initials: RA
authors.lastname: Nicoll
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000502:physiology; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D063388:Endocannabinoids; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D006624:Hippocampus / Q000502:physiology*; D066298:In Vitro Techniques; D007395:Interneurons / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology*; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017661:Receptors, Presynaptic / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D063388:Endocannabinoids; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D017661:Receptors, Presynaptic; D005576:Colforsin; D019204:GTP-Binding Proteins