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

Key points: Inhibition of synaptic responses by activation of presynaptic cannabinoid type-1 (Cb1) receptors is reduced at parallel fibre synapses in the cerebellum following 4 Hz stimulation. Activation of adenylyl cyclase is necessary and sufficient for down-regulation of Cb1 receptors induced by 4 Hz stimulation. 4 Hz stimulation reduces Cb1 receptor function by (i) increasing the rate of endocannabinoid clearance from the synapse and (ii) decreasing expression of Cb1 receptors. Abstract: 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 4 Hz 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.