J Physiol. 2019 Apr 25.
KEY POINTS: Inhibition of synaptic responses by activation of presynaptic cannabinoid type-1 (Cb1) receptors is reduced at parallel fiber 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 1) increasing the rate of endocannabinoid clearance from the synapse, 2) decreasing expression of Cb1 receptors.ABSTRACT: Cannabinoid type-1 receptors (Cb1R) are expressed in the presynaptic membrane of many synapses, including parallel fiber-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 fiber 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 due to reduced expression of Cb1Rs and increased degradation of endocannabinoids by MAGL. Long-term changes in presynaptic Cb1R expression may alter other forms of Cb1R-dependent plasticity at parallel fiber synapses, priming or inhibiting the circuit for associative learning. This article is protected by copyright. All rights reserved.