Increased reluctant vesicles underlie synaptic depression by GPR55 in axon terminals of cerebellar Purkinje cells

Control of synaptic transmission efficacy by neuronal activity and neuromodulators is pivotal for brain function. Synaptic suppression by cannabinoids activating CB1 receptors has been extensively studied at the molecular and cellular levels to understand the neuronal basis for effects of cannabis intake. Here, we focused on GPR55, non-canonical type of cannabinoid receptor, which shows sensitivity to cannabidiol included in cannabis, aiming to highlight its actions on presynaptic function. Taking advantage of direct patch-clamp recordings from axon terminals of cerebellar Purkinje cells together with fluorescent imaging of vesicular exocytosis using synapto-pHluorin, we show that GPR55 suppresses synaptic transmission as CB1 receptor does, but through a distinct presynaptic modulation of release machinery. Activation of GPR55 reduced transmitter release by changing neither presynaptic action potential waveform nor Ca2+ influx, but by making a large population of Ca2+-responsive synaptic vesicles insensitive to Ca2+ influx through voltage-gated Ca2+ channels, leading to substantial reduction of the readily releasable pool of vesicles. Thus, the present study identifies a unique mechanism to suppress presynaptic transmitter release by an atypical cannabinoid receptor GPR55, which would enable subtype-specific modulation of neuronal computation by cannabinoid receptors.