4.7 Article

Serotonin evokes endocannabinoid release and retrogradely suppresses excitatory synapses

Journal

JOURNAL OF NEUROSCIENCE
Volume 28, Issue 25, Pages 6508-6515

Publisher

SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0678-08.2008

Keywords

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

Categories

Funding

  1. NIDA NIH HHS [R01 DA024090, R01 DA024090-07, R01DA024090] Funding Source: Medline
  2. NINDS NIH HHS [R01 NS032405, T32 NS007484, T32 NS007484-09] Funding Source: Medline

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5-HT2-type serotonin receptors (5-HT(2)Rs) are widely expressed throughout the brain and mediate many of the modulatory effects of serotonin. It has been thought that postsynaptic 5-HT(2)Rs act primarily by depolarizing neurons and thereby increasing their excitability. However, it is also known that 5-HT(2)Rs 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 (CB(1)Rs). Here, we examine whether activation of 5-HT(2)Rs can regulate synapses through such a mechanism by studying excitatory synapses onto cells in the inferior olive (IO). These cells express 5-HT(2)Rs 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-HT(2)Rs and 5-HT(1B)Rs contribute to this modulation by decreasing the probability of glutamate release from presynaptic boutons. The suppression by 5-HT(2)Rs is of particular interest because it is prevented by CB1R antagonists, and 5-HT(2)Rs are thought to be located only postsynaptically on IO cells. Our results indicate that serotonin activates 5-HT(2)Rs on IO neurons, thereby releasing endocannabinoids that act retrogradely to suppress glutamate release by activating presynaptic CB(1)Rs. These findings establish a link between serotonin signaling and endocannabinoid signaling. Based on the extensive distribution of 5-HT(2)Rs and CB1Rs, it seems likely that this mechanism could mediate many of the actions of 5-HT(2)Rs throughout the brain.

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