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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Calcium Channel Blockers / pharmacology
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Calcium Channels / physiology
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Cannabinoid Receptor Modulators
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Cannabinoids / metabolism*
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Colforsin / pharmacology
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Endocannabinoids
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Female
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GTP-Binding Proteins / metabolism
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Hippocampus / physiology*
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In Vitro Techniques
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Interneurons / physiology
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Patch-Clamp Techniques
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Presynaptic Terminals / drug effects
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Presynaptic Terminals / physiology*
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Pyramidal Cells / drug effects
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Pyramidal Cells / physiology*
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Rats
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Rats, Sprague-Dawley
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Receptors, Cannabinoid
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Receptors, Drug / deficiency
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Receptors, Drug / genetics
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Receptors, Drug / physiology*
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Receptors, Presynaptic / drug effects
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Receptors, Presynaptic / physiology*
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Signal Transduction
Substances
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Calcium Channel Blockers
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Calcium Channels
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Cannabinoid Receptor Modulators
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Cannabinoids
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Endocannabinoids
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Receptors, Cannabinoid
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Receptors, Drug
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Receptors, Presynaptic
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Colforsin
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GTP-Binding Proteins