Long-term depression of presynaptic cannabinoid receptor function at parallel fibre synapses.

Abstract

Inhibition of synaptic responses by activation of presynaptic cannabinoid type-1 (Cb1) receptors is reduced at parallel fibre synapses in the cerebellum following 4Hz stimulation. Activation of adenylyl cyclase is necessary and sufficient for down-regulation of Cb1 receptors induced by 4Hz stimulation. 4Hz stimulation reduces Cb1 receptor function by (i) increasing the rate of endocannabinoid clearance from the synapse and (ii) decreasing expression of Cb1 receptors. Cannabinoid type-1 receptors (Cb1R) are expressed in the presynaptic membrane of many synapses, including parallel fibre-Purkinje cell synapses in the cerebellum, where they are involved in short- and long-term plasticity of synaptic responses. We show that Cb1R expression itself is a plastic property of the synapse regulated by physiological activity patterns. We made patch clamp recordings from Purkinje cells in cerebellar slices and assessed Cb1R activity by measuring depolarization-induced suppression of excitation (DSE). We find that DSE is normally stable at parallel fibre synapses but, following 4Hz stimulation, DSE is persistently reduced and recovers more rapidly. Using a combination of electrophysiology, pharmacology and biochemistry, we show that changes in DSE are a result of the reduced expression of Cb1Rs and increased degradation of endocannabinoids by monoacylglycerol lipase. Long-term changes in presynaptic Cb1R expression may alter other forms of Cb1R-dependent plasticity at parallel fibre synapses, priming or inhibiting the circuit for associative learning.