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Serotonin Evokes Endocannabinoid Release and Retrogradely Suppresses Excitatory Synapses

5-HT2-type serotonin receptors (5-HT2Rs) are widely expressed throughout the brain and mediate many of the modulatory effects of serotonin. It has been thought that postsynaptic 5-HT2Rs act primarily by depolarizing neurons and thereby increasing their excitability. However, it is also known that 5-HT2Rs are coupled to Gq/11-type G-proteins and that some other types of Gq/11-coupled receptors can regulate synapses by evoking endocannabinoid release and activating presynaptic cannabinoid-type 1 receptors (CB1Rs). Here, we examine whether activation of 5-HT2Rs can regulate synapses through such a mechanism by studying excitatory synapses onto cells in the inferior olive (IO). These cells express 5-HT2Rs on their soma and dendrites, and the IO receives extensive serotonergic input. We find that the excitatory synaptic inputs onto IO cells are strongly suppressed by serotonin receptor agonists as well as release of endogenous serotonin. Both 5-HT2Rs and 5-HT1BRs contribute to this modulation by decreasing the probability of glutamate release from presynaptic boutons. The suppression by 5-HT2Rs is of particular interest because it is prevented by CB1R antagonists, and 5-HT2Rs are thought to be located only postsynaptically on IO cells. Our results indicate that serotonin activates 5-HT2Rs on IO neurons, thereby releasing endocannabinoids that act retrogradely to suppress glutamate release by activating presynaptic CB1Rs. These findings establish a link between serotonin signaling and endocannabinoid signaling. Based on the extensive distribution of 5-HT2Rs and CB1Rs, it seems likely that this mechanism could mediate many of the actions of 5-HT2Rs throughout the brain.