LAUSR

ABSTRACT Endogenous cannabinoids are diffusible lipid ligands of the main cannabinoid receptors type 1 and 2 (CB1R and CB2R). In the central nervous system endocannabinoids are produced in an activity‐dependent manner and have been identified as retrograde modulators of synaptic transmission. Additionally, some neurons display a cell‐autonomous slow self‐inhibition (SSI) mediated by endocannabinoids. In these neurons, repetitive action potential firing triggers the production of endocannabinoids, which induce a long‐lasting hyperpolarization of the membrane potential, rendering the cells less excitable. Different endocannabinoid receptors and effector mechanisms have been described underlying SSI in different cell types and brain areas. Here, we investigate SSI in neurons of layer 2/3 in the somatosensory cortex. High‐frequency bursts of action potentials induced SSI in pyramidal cells (PC) and regular spiking non‐pyramidal cells (RSNPC), but not in fast‐spiking interneurons (FS). In RSNPCs the hyperpolarization was accompanied by a change in input resistance due to the activation of G protein‐coupled inward‐rectifying K+ (GIRK) channels. A CB2R‐specific agonist induced the long‐lasting hyperpolarization, whereas preincubation with a CB2R‐specific inverse agonist suppressed SSI. Additionally, using cannabinoid receptor knockout mice, we found that SSI was still intact in CB1R‐deficient but abolished in CB2R‐deficient mice. Taken together, we describe an additional SSI mechanism in which the activity‐induced release of endocannabinoids activates GIRK channels via CB2Rs. These findings expand our knowledge about cell type‐specific differential neuronal cannabinoid receptor signaling and suggest CB2R‐selective compounds as potential therapeutic approaches. HIGHLIGHTSTrains of APs induce a long‐lasting hyperpolarization in pyramidal cells and regular spiking non‐pyramidal cells but not in fastspiking interneurons.SSI is mediated by activation of GIRK channels.Activation of CB2Rs mediate SSI.