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The Journal of Neuroscience, June 18, 2008, 28(25):6508-6515; doi:10.1523/JNEUROSCI.0678-08.2008

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Cellular/Molecular
Serotonin Evokes Endocannabinoid Release and Retrogradely Suppresses Excitatory Synapses

Aaron R. Best and Wade G. Regehr

Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115

Correspondence should be addressed to Wade G. Regehr, Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115. Email: wade_regehr{at}hms.harvard.edu

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 G_q/11-type G-proteins and that some other types of G_q/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-HT_1BRs 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.

Key words: synaptic plasticity; serotonin; endocannabinoid; inferior olive; retrograde inhibition; 5-HT₂ receptor

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Received Oct. 25, 2007; revised May 19, 2008; accepted May 20, 2008.

Correspondence should be addressed to Wade G. Regehr, Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115. Email: wade_regehr{at}hms.harvard.edu

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