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.