Distinct endocannabinoid control of GABA release at perisomatic and dendritic synapses in the hippocampus

Endocannabinoid-mediated retrograde synaptic signaling is a key regulator of GABA release at synapses formed on the perisomatic region of pyramidal cells by basket cells that coexpress the cannabinoid type 1 receptor (CB1R) and cholecystokinin (CCK). However, CB1R and CCK-positive GABAergic terminals are present on pyramidal cell dendrites as well, but the principles of endocannabinoid control of GABA release in dendrites are not understood. We performed paired recordings from CCK-positive perisomatically (basket cells) or dendritically projecting (Schaffer collateral-associated cells) interneurons and postsynaptic CA1 pyramidal cells to determine the properties of endocannabinoid signaling at GABAergic synapses along the somato-dendritic axis. Although several key elements of the currently known molecular machinery for endocannabinoid synthesis are thought be primarily localized in dendrites, our results revealed that the depolarization-induced suppression of inhibition, the endocannabinoid-mediated tonic inhibition of GABA release, and the metabotropic glutamate receptor activation-induced, CB₁R-mediated depression of GABA release were all significantly less effective at dendritic compared with perisomatic synapses. In addition, low concentration of exogenous CB₁ receptor agonist inhibited GABA release to a lesser extent at dendritic compared with perisomatic synapses, indicating that presynaptic differences are partly responsible for the differential control of GABA release by endocannabinoids in dendrites. Together, these data demonstrate a novel domain-specific regulation of GABA release by endocannabinoid signaling in the hippocampus.