Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations

Using a new antibody developed against the C-terminus of the cannabinoid re ceptor (CBI), the immunostaining in the hippocampus revealed additional axo n terminals relative to the pattern reported previously with an N-terminus antibody. Due to a greater sensitivity of this antibody, a large proportion of boutons in the dendritic layers displaying symmetrical (GABAergic) syna pses were also strongly immunoreactive for CB1 receptors, as were axon term inals of perisomatic inhibitory cells containing cholecystokinin. Asymmetri cal (glutamatergic) synapses, however, were always negative for CB1. To inv estigate the effect of presynaptic CB1 receptor activation on hippocampal i nhibition, we recorded inhibitory postsynaptic currents (IPSCs) from princi pal cells. Bath application of CB1 receptor agonists (WIN55,212-2 and CP55, 940) suppressed IPSCs evoked by local electrical stimulation, which could b e prevented or reversed by the CB1 receptor antagonist SR141716A. Action po tential-driven IPSCs, evoked by pharmacological stimulation of a subset of interneurons, were also decreased by CB1 receptor activation. We also exami ned the effects of CB1 receptor agonists on Ca2+-independent miniature IPSC s (mlPSC). Both agonists were without significant effect on the frequency o r amplitude of mlPSCs. Synchronous gamma oscillations induced by kainic aci d in the CA3 region of hippocampal slices were reversibly reduced in amplit ude by the CB1 receptor agonist CP 55,940, which is consistent with an acti on on IPSCs. We used CB1(-/-) knock-out mice to confirm the specificity of the antibody and of the agonist (WIN55,212-2) action. We conclude that acti vation of presynaptic CB1 receptors decreases Ca2+-dependent GABA release, and thereby reduces the power of hippocampal network oscillations.