Postsynaptic origin of CB1-dependent tonic inhibition of GABA release at cholecystokinin-positive basket cell to pyramidal cell synapses in the CA1 region of the rat hippocampus.

Cholecystokinin-positive (CCK+) basket cells are a major source of perisomatic GABAergic inputs to CA1 pyramidal cells. These interneurons express high levels of presynaptic cannabinoid type 1 (CB1) receptors that mediate short-term depression of GABA release following depolarization of postsynaptic cells. However, it is not known whether GABA release from CA1 CCK+ basket cells is under tonic endocannabinoid inhibition. In paired patch-clamp recordings, action potentials in presynaptic CCK+ basket cells evoked large IPSCs with fast kinetics in pyramidal cells. The proportion of action potentials that failed to evoke GABA release varied markedly between pairs, from highly reliable to virtually silent connections. Application of the CB1 receptor antagonist AM251 (10 microm) decreased the proportion of failures, revealing a persistent suppression of synaptic transmission by CB1 receptors. However, AM251 had no significant effect on the failure rate when the calcium chelator BAPTA (10 mm) was introduced into the postsynaptic cell, indicating that the tonic inhibition of GABA release by CB1 receptors is homosynaptically controlled by the postsynaptic cell, and that it is not due to constitutive CB1 receptor activity. Application of muscarinic or metabotropic glutamate receptor agonists inhibited synaptic transmission exclusively through the release of endocannabinoids from postsynaptic cells in a manner that could not be blocked by postsynaptic BAPTA, and had no direct effect on transmission. In contrast, GABA(B) receptor activation directly blocked GABA release, but there was no evidence for tonic inhibition of GABA release by GABA(B) receptors. Neither serotonergic nor mu-opioid agonists had significant influence on GABA release from CCK+ axon terminals. These results reveal that GABA release from CA1 CCK+ basket cells is under homosynaptic tonic inhibition by endocannabinoids, and it is subject to both direct and indirect modulation by various G-protein-dependent neuromodulators.