Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells

Brief depolarization of cerebellar Purkinje cells was found to inhibit para llel fiber and climbing fiber EPSCs for tens of seconds. This depolarizatio n-induced suppression of excitation (DSE) is accompanied by altered paired- pulse plasticity, suggesting a presynaptic locus. Fluorometric imaging reve aled that postsynaptic depolarization also reduces presynaptic calcium infl ux. The inhibition of both presynaptic calcium influx and EPSCs is eliminat ed by buffering postsynaptic calcium with BAPTA. The cannabinoid CB1 recept or antagonist AM251 prevents DSE, and the agonist WIN 55,212-2 occludes DSE . These findings suggest that Purkinje cells release endogenous cannabinoid s in response to elevated calcium, thereby inhibiting presynaptic calcium e ntry and suppressing transmitter release. DSE may provide a way for cells t o use their firing rate to dynamically regulate synaptic inputs. Together w ith previous studies, these findings suggest a widespread role for endogeno us cannabinoids in retrograde synaptic inhibition.