Cerebellar depolarization-induced suppression of inhibition is mediated by endogenous cannabinoids

Depolarization of cerebellar Purkinje neurons transiently suppresses IPSCs through a process known as depolarization-induced suppression of inhibition (DSI). This IPSC suppression occurs presynaptically and results from an unknown retrograde signal released from Purkinje cells. We recorded IPSCs from voltage-clamped Purkinje cells in cerebellar brain slices to identify the retrograde signal for cerebellar DSI. We find that DSI persists in the presence of the broad-spectrum metabotropic glutamate receptor antagonist LY341495 and the GABA(B) receptor antagonist CGP55845, suggesting that the retrograde signal is not acting through these receptors. However, an antagonist of the cannabinoid CB1 receptor AM251 completely blocked cerebellar DSI. Additionally, the cannabinoid receptor agonist WIN55,212-2 suppressed IPSCs and occluded any additional IPSC reduction by DSI. These results indicate that cannabinoids released from Purkinje cells after depolarization activate CB1 receptors on inhibitory neurons and suppress IPSCs for tens of seconds. Cerebellar DSI thus shares a common retrograde messenger with DSI in the hippocampus and depolarization-induced suppression of excitation in the cerebellum, suggesting that retrograde synaptic suppression by endogenous cannabinoids represents a widespread signaling mechanism.