Cannabinoid type 2 receptors inhibit GABA_A receptor-mediated currents in cerebellar Purkinje cells of juvenile mice

Signaling through the endocannabinoid system is critical to proper functioning of the cerebellar circuit. However, most studies have focused on signaling through cannabinoid type 1 (CB1) receptors, while relatively little is known about signaling through type 2 (CB2) receptors. We show that functional CB2 receptors are expressed in Purkinje cells using a combination of immunohistochemistry and patch-clamp electrophysiology in juvenile mice. Pharmacological activation of CB2 receptors significantly reduces inhibitory synaptic responses and currents mediated by photolytic uncaging of RuBi-GABA in Purkinje cells. CB2 receptor activation does not change the paired-pulse ratio of inhibitory responses and its effects are blocked by inclusion of GDP-β-S in the internal solution, indicating a postsynaptic mechanism of action. However, CB2 receptors do not contribute to depolarization induced suppression of inhibition (DSI), indicating they are not activated by endocannabinoids synthesized and released from Purkinje cells using this protocol. This work demonstrates that CB2 receptors inhibit postsynaptic GABA_A receptors by a postsynaptic mechanism in Purkinje cells. This represents a novel mechanism by which CB2 receptors may modulate neuronal and circuit function in the central nervous system.