Tonic endocannabinoid-mediated modulation of GABA release is independent of the CB(1) content of axon terminals

The release of GABA from cholecystokinin-containing interneurons is modulated by type-1 cannabinoid receptors (CB(1)). Here we tested the hypothesis that the strength of CB(1)-mediated modulation of GABA release is related to the CB(1) content of axon terminals. Basket cell boutons have on average 78% higher CB(1) content than those of dendritic-layer-innervating (DLI) cells, a consequence of larger bouton surface and higher CB(1) density. The CB(1) antagonist AM251 caused a 54% increase in action potential-evoked [Ca(2+)] in boutons of basket cells, but not in DLI cells. However, the effect of AM251 did not correlate with CB(1) immunoreactivity of individual boutons. Moreover, a CB(1) agonist decreased [Ca(2+)] in a cell type- and CB(1)-content-independent manner. Replica immunogold labelling demonstrated the colocalization of CB(1) with the Cav2.2 Ca(2+) channel subunit. Our data suggest that only a subpopulation of CB(1)s, within nanometre distances from their target Cav2.2 channels, are responsible for endocannabinoid-mediated modulation of GABA release.