Serotonin evokes endocannabinoid release and retrogradely suppresses excitatory synapses
Serotonin evokes endocannabinoid release and retrogradely suppresses excitatory synapses
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DOI：
10.1523/jneurosci.0678-08.2008
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发表时间：
2008-06-18
影响因子：
5.3
通讯作者：
Regehr, Wade G.
中科院分区：
文献类型：
--
作者：
Best, Aaron R.;Regehr, Wade G.
5-HT 2型5-羟色胺受体（5-HT（2）Rs）在整个大脑中广泛表达，并介导5-羟色胺的许多调节作用。一般认为，突触后5-HT（2）Rs主要通过使神经元去极化，从而增加其兴奋性而起作用。然而，我们也知道5-HT（2）Rs与G（q/11）型G蛋白偶联，并且一些其他类型的G（q/11）偶联受体可以通过诱发内源性大麻素释放和激活突触前大麻素1型受体（CB（1）Rs）来调节突触。在此，我们通过研究下橄榄核（IO）细胞上的兴奋性突触来研究5-HT（2）Rs的激活是否可以通过这种机制调节突触。这些细胞在其索马和树突上表达5-HT（2）Rs，IO接受广泛的多巴胺能输入。我们发现，到IO细胞的兴奋性突触输入强烈抑制5-羟色胺受体激动剂以及内源性5-羟色胺的释放。5-HT（2）Rs和5-HT（1B）Rs通过降低突触前终扣释放谷氨酸的可能性而参与这种调节。5-HT（2）Rs的抑制作用特别令人感兴趣，因为它被CB 1 R拮抗剂所阻止，并且5-HT（2）Rs被认为仅位于IO细胞的突触后。我们的研究结果表明，5-羟色胺激活IO神经元上的5-HT（2）受体，从而释放内源性大麻素，这些内源性大麻素通过激活突触前CB（1）受体来逆行抑制谷氨酸的释放。这些发现建立了5-羟色胺信号和内源性大麻素信号之间的联系。基于5-HT（2）Rs和CB 1 Rs的广泛分布，似乎该机制可以介导5-HT（2）Rs在整个脑中的许多作用。
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.