Control of inhibition by the direct action of cannabinoids on GABA_A receptors

Cannabinoids are known to regulate inhibitory synaptic transmission via activation of presynaptic G protein-coupled cannabinoid CB₁ receptors (CB₁Rs). Additionally, recent studies suggest that cannabinoids can also directly interact with recombinant GABA_A receptors (GABA_ARs), potentiating currents activated by micromolar concentrations of γ-aminobutyric acid (GABA). However, the impact of this direct interaction on GABAergic inhibition in central nervous system is unknown. Here we report that currents mediated by recombinant GABA_ARs activated by high (synaptic) concentrations of GABA as well as GABAergic inhibitory postsynaptic currents (IPSCs) at neocortical fast spiking (FS) interneuron to pyramidal neuron synapses are suppressed by exogenous and endogenous cannabinoids in a CB₁R-independent manner. This IPSC suppression may account for disruption of inhibitory control of pyramidal neurons by FS interneurons. At FS interneuron to pyramidal neuron synapses, endocannabinoids induce synaptic low-pass filtering of GABA_AR-mediated currents evoked by high-frequency stimulation. The CB₁R-independent suppression of inhibition is synapse specific. It does not occur in CB₁R containing hippocampal cholecystokinin-positive interneuron to pyramidal neuron synapses. Furthermore, in contrast to synaptic receptors, the activity of extrasynaptic GABA_ARs in neocortical pyramidal neurons is enhanced by cannabinoids in a CB₁R-independent manner. Thus, cannabinoids directly interact differentially with synaptic and extrasynaptic GABA_ARs, providing a potent novel context-dependent mechanism for regulation of inhibition.