A selective 5-HT1a receptor agonist improves respiration in a mouse model of Rett syndrome
A selective 5-HT1a receptor agonist improves respiration in a mouse model of Rett syndrome
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DOI：
10.1152/japplphysiol.00889.2013
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发表时间：
2013-12-01
影响因子：
3.3
通讯作者：
Bissonnette, John M.
中科院分区：
文献类型：
--
作者：
Levitt, Erica S.;Hunnicutt, Barbara J.;Bissonnette, John M.
Rett综合征是一种神经系统疾病，由编码DNA结合蛋白甲基-CpG结合蛋白2（Mecp 2）的基因功能缺失突变引起。该综合征的一个突出特征是呼吸紊乱，其特征是频繁的呼吸暂停和不规则的呼吸间隔周期。8-羟基-2-二丙基氨基四氢化萘已经显示出正调节这些紊乱（Abdala AP，Dutschmann M，Bissonnette JM，Paton JF，Proc Natl Acad Sci U S A 107：18208-18213，2010），但是作用模式尚不清楚。在这里，我们表明，选择性5-HT 1a偏向激动剂3-氯-4-氟苯基-（4-氟-4-{[（5-甲基嘧啶-2-基甲基）-氨基]-甲基}-哌啶-1-基）-甲酮（F15599）减少呼吸暂停和纠正不规则的杂合Mecp 2缺陷型雌性和Mecp 2缺失型雄性小鼠。在中缝背核神经元的全细胞电压钳记录中，F15599有效地诱导了一个外向电流，该电流被钡阻断，在钾平衡电位处逆转，并被5-HT 1a拮抗剂WAY 100135拮抗。这与体树突5-HT 1a受体介导的G蛋白偶联内向整流钾通道（GIRK）激活一致。与此相反，F15599没有激活5-HT 1b/d受体介导的抑制谷氨酸释放从终端在突触前机制的脑桥核。因此，F15599激活体树突5-HT 1a自身受体，但不激活轴突5-HT 1b/d受体。在未麻醉的Mecp 2缺陷杂合子雌性小鼠中，F15599以剂量依赖性方式减少呼吸暂停，0.1 mg/kg时的最大效应为74.5 +/- 6.9%，并改善呼吸暂停规律性。同样，在Mecp 2基因敲除雄性小鼠中，0.25 mg/kg剂量下呼吸暂停减少62 +/- 6.6%，呼吸变得规律。结果表明，5-HT 1a激动剂可以改善呼吸，激活GIRK通道而不影响神经递质的释放。
Rett syndrome is a neurological disorder caused by loss of function mutations in the gene that encodes the DNA binding protein methyl-CpG- binding protein 2 (Mecp2). A prominent feature of the syndrome is disturbances in respiration characterized by frequent apnea and an irregular interbreath cycle. 8-Hydroxy-2-dipropylaminotetralin has been shown to positively modulate these disturbances (Abdala AP, Dutschmann M, Bissonnette JM, Paton JF, Proc Natl Acad Sci U S A 107: 18208-18213, 2010), but the mode of action is not understood. Here we show that the selective 5-HT1a biased agonist 3-chloro-4-fluorophenyl-(4-fluoro-4-{[(5-methylpyrimidin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl)-methanone(F15599) decreases apnea and corrects irregularity in both heterozygous Mecp2-deficient female and in Mecp2 null male mice. In whole cell voltage-clamp recordings from dorsal raphe neurons, F15599 potently induced an outward current, which was blocked by barium, reversed at the potassium equilibrium potential, and was antagonized by the 5-HT1a antagonist WAY100135. This is consistent with somatodendritic 5-HT1a receptor-mediated activation of G protein-coupled inwardly rectifying potassium channels (GIRK). In contrast, F15599 did not activate 5-HT1b/d receptors that mediate inhibition of glutamate release from terminals in the nucleus accumbens by a presynaptic mechanism. Thus F15599 activated somatodendritic 5-HT1a autoreceptors, but not axonal 5-HT1b/d receptors. In unanesthetized Mecp2-deficient heterozygous female mice, F15599 reduced apnea in a dose-dependent manner with maximal effect of 74.5 +/- 6.9% at 0.1 mg/kg and improved breath irrregularity. Similarly, in Mecp2 null male mice, apnea was reduced by 62 +/- 6.6% at 0.25 mg/kg, and breathing became regular. The results indicate respiration is improved with a 5-HT1a agonist that activates GIRK channels without affecting neurotransmitter release.