Conservation of 5-HT1A receptor-mediated autoinhibition of serotonin (5-HT) neurons in mice with altered 5-HT homeostasis
Conservation of 5-HT1A receptor-mediated autoinhibition of serotonin (5-HT) neurons in mice with altered 5-HT homeostasis
复制标题
DOI：
10.3389/fphar.2013.00097
复制
发表时间：
2013-01-01
影响因子：
5.6
通讯作者：
Corradetti, Renato
中科院分区：
文献类型：
--
作者：
Araragi, Naozumi;Mlinar, Boris;Corradetti, Renato
中缝背核(DRN)内5-羟色胺(5-HT)神经元的放电活动受抑制性5-HT1a自身受体的控制。这种自我抑制机制与焦虑和抑郁等情绪调节障碍的病因学以及抗抑郁作用的机制有关。在这里，我们研究了两种缺乏5-羟色胺能传递关键中介的转基因小鼠模型：5-羟色胺转运体基因敲除(Sert-/-)和色氨酸羟化酶-2基因敲除(TPH2-/-)小鼠，大脑5-羟色胺可获得性的持续变化如何影响自身抑制。在DRN切片上，通过松散密封的细胞附着记录来评估自身抑制的程度。首先，应用5-HT1a选择性激动剂R(+)-8-羟基-2-(二正丙氨基)四氢呋喃对TPH2-/-小鼠和Sert-/-小鼠的5-HT1a受体分别表现出轻微的增敏和显著的减敏作用。虽然来自Tph2-/-小鼠的5-羟色胺神经元对L-色氨酸的反应没有表现出自身抑制，但在Sert-/-小鼠中，这些神经元的自抑制作用没有改变，尽管它们的5-HI1a自身受体显著脱敏。当应用5-羟基-L色氨酸(5-HIP)绕过Tph2依赖的5-羟色胺合成步骤时，与野生型对照相比，Tph2-/-和Sert-/-小鼠的神经元在显著低于野生型对照的5-HIP浓度下都降低了放电频率。我们的发现表明，与流行的观点相反，躯体树突状细胞5-HT1a受体的敏感性并不能预测5-羟色胺神经元自身抑制的程度。5-HT1a受体敏感性的改变可能更多地被视为一种适应性机制，以保持自身抑制功能，以响应因5-羟色胺能信号介体靶向失活而导致的细胞外5-羟色胺水平的极大变化。
Firing activity of serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) is controlled by inhibitory somatodendritic 5-HT1A autoreceptors. This autoinhibitory mechanism is implicated in the etiology of disorders of emotion regulation, such as anxiety disorders and depression, as well as in the mechanism of antidepressant action. Here, we investigated how persistent alterations in brain 5-HT availability affect autoinhibition in two genetically modified mouse models lacking critical mediators of serotonergic transmission: 5-HT transporter knockout (Sert-/-) and tryptophan hydroxylase-2 knockout (Tph2-/-) mice. The degree of autoinhibition was assessed by loose-seal cell-attached recording in DRN slices. First, application of the 5-HT1A-selective agonist R(+)-8-hydroxy-2-(di-n-propylamino)tetralin showed mild sensitization and marked desensitization of 5-HT1A receptors in Tph2-/- mice and Sert-/- mice, respectively. While 5-HT neurons from Tph2-/- mice did not display autoinhibition in response to L-tryptophan, autoinhibition of these neurons was unaltered in Sert-/- mice despite marked desensitization of their 5-HI1A autoreceptors. When the Tph2-dependent 5-HT synthesis step was bypassed by application of 5-hydroxy-L-tryptophan (5-HIP), neurons from both Tph2-/- and Sert-/- mice decreased their firing rates at significantly lower concentrations of 5-HIP compared to wildtype controls. Our findings demonstrate that, as opposed to the prevalent view, sensitivity of somatodendritic 5-HT1A receptors does not predict the magnitude of 5-HT neuron autoinhibition. Changes in 5-HT1A receptor sensitivity may rather be seen as an adaptive mechanism to keep autoinhibition functioning in response to extremely altered levels of extracellular 5-HT resulting from targeted inactivation of mediators of serotonergic signaling.