Endocannabinoids mediate the glucocorticoid-induced inhibition of excitatory synaptic transmission to dorsal raphe serotonin neurons.
Endocannabinoids mediate the glucocorticoid-induced inhibition of excitatory synaptic transmission to dorsal raphe serotonin neurons.
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内源性大麻素介导糖皮质激素诱导的对中缝背侧血清素神经元兴奋性突触传递的抑制。
DOI：
10.1113/jphysiol.2012.238659
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Haj-Dahmane,Samir
中科院分区：
文献类型：
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作者：
Wang,Jue;Shen,Roh-Yu;Haj-Dahmane,Samir
关键点·糖皮质激素对5-羟色胺系统的调节在应激反应的调节中起着核心作用。然而，糖皮质激素调节中缝背侧5-羟色胺神经元兴奋性的机制尚不清楚。·在这项研究中，我们表明，糖皮质激素通过减少谷氨酸释放，迅速抑制谷氨酸能突触传递到5-羟色胺神经元。·谷氨酸释放的快速抑制不是由经典的细胞内糖皮质激素受体发出的，而是通过推测的膜定位G蛋白偶联受体。·激活位于膜位置的G-蛋白偶联受体增加内源性大麻信号，进而调节背侧中缝谷氨酸能传递的抑制。糖皮质激素通过抑制环氧合酶-2而增加内源性大麻素的张力。摘要糖皮质激素通过调节5-羟色胺(5-HT)系统的功能，在应激反应的调节中发挥重要作用。然而，糖皮质激素对中缝背核(DR)5-羟色胺(5-HT)神经元兴奋性的确切影响尚不清楚。在这项研究中，我们研究了糖皮质激素对兴奋性突触传递到可能的DR5-羟色胺神经元的影响。我们发现皮质酮或合成的糖皮质激素激动剂地塞米松通过抑制DR的谷氨酸释放而迅速抑制谷氨酸能突触传递到DR的5-羟色胺神经元，这种抑制作用被膜不通透性的糖皮质激素所模拟，表明膜定位的皮质类固醇受体参与了这种抑制作用。糖皮质激素对谷氨酸能传递的抑制作用是通过激活突触后G蛋白偶联受体和逆行内源性大麻素(ECB)信使来实现的。对下游机制的研究表明，糖皮质激素通过抑制环氧合酶-2来增强ECB的信号转导。总之，这些发现揭示了糖皮质激素控制DR 5-羟色胺神经元兴奋性的新机制，并为应激激素对5-羟色胺系统功能的快速影响提供了新的见解。
Key points•The modulation of the serotonin system by glucocorticoids plays a central role in the regulation of stress responses. However, the mechanisms by which glucocorticoids regulate the excitability of dorsal raphe serotonin neurons remain unknown.•In this study, we show that glucocorticoids rapidly inhibit glutamatergic synaptic transmission to serotonin neurons by reducing glutamate release.•The rapid inhibition of glutamate release is not signalled by classical intracellular glucocorticoid receptors, but rather by putative membrane‐located G‐protein‐coupled receptors.•Activation of the membrane‐located G‐protein‐coupled receptors increases endocannabinoid signalling, which in turn mediates the inhibition of glutamatergic transmission in the dorsal raphe.•In the dorsal raphe, glucocorticoids increase endocannabinoid tone by inhibiting cyclooxygenase‐2.AbstractGlucocorticoids play a critical role in the modulation of stress responses by controlling the function of the serotonin (5‐HT) system. However, the precise effects of glucocorticoids on the excitability of dorsal raphe (DR) 5‐HT neurons remain unknown. In this study, we investigated the effects of glucocorticoids on excitatory synaptic transmission to putative DR 5‐HT neurons. We found that corticosterone or the synthetic glucocorticoid agonist dexamethasone rapidly suppressed glutamatergic synaptic transmission to DR 5‐HT neurons by inhibiting glutamate release in the DR. This inhibitory effect was mimicked by membrane‐impermeable glucocorticoids, indicating the involvement of membrane‐located corticosteroid receptors. The glucocorticoid‐induced inhibition of glutamatergic transmission was mediated by the activation of postsynaptic G‐protein‐coupled receptors and signalled by retrograde endocannabinoid (eCB) messengers. Examination of the downstream mechanisms revealed that glucocorticoids enhance eCB signalling via an inhibition of cyclooxygenase‐2. Together, these findings unravel a novel mechanism by which glucocorticoids control the excitability of DR 5‐HT neurons and provide new insight into the rapid effects of stress hormones on the function of the 5‐HT system.