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 medi ate the suppression of GABA release that follows depolarization of a hippoc ampal CA1 pyramidal neuron-termed "depolarization-induced suppression of in hibition" (DSI). Here, we report that DSI is absent in mice which lack cann abinoid receptor-1 (CB1). Pharmacological and kinetic evidence suggests tha t CB1 activation inhibits presynaptic Ca2+ channels through direct G protei n inhibition. Paired recordings show that endocannabinoids selectively inhi bit a subclass of synapses distinguished by their fast kinetics and large u nitary conductance. Furthermore, cannabinoid-sensitive inputs are unusual a mong central nervous system synapses in that they use N- but not P/Q-type C a2+ channels for neurotransmitter release. These results indicate that endo cannabinoids are highly selective, rapid modulators of hippocampal inhibiti on.