Presynaptic specificity of endocannabinoid signaling in the hippocampus.
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.
Wilson
R I
RI
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, 94143, USA.
Kunos
G
G
Nicoll
R A
RA
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
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