Phosphorylation of MeCP2 at Ser421 contributes to chronic antidepressant action.
Phosphorylation of MeCP2 at Ser421 contributes to chronic antidepressant action.
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DOI：
10.1523/jneurosci.2156-12.2012
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发表时间：
2012-10-10
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影响因子：
--
通讯作者：
West AE
中科院分区：
文献类型：
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作者：
Hutchinson AN;Deng JV;Cohen S;West AE
虽然三环类抗抑郁药能迅速激活单胺类神经传递，但这些药物必须长期服用才能缓解抑郁症状。这一观察表明，单胺受体激活下游的分子机制，包括基因转录的诱导，是慢性抗抑郁药诱导行为变化的基础。在这里，我们展示了甲基-CpG结合蛋白2(MeCP2)调节对慢性抗抑郁药物治疗的行为反应。丙咪嗪可选择性地在伏隔核和外侧缰核诱导MeCP2在Ser421(PMeCP2)的磷酸化，这两个区域是大脑中对抑郁样行为重要的区域。为了测试pMeCP2在抑郁样行为中的作用，我们使用了携带胚系突变的雄性小鼠，这些突变敲入了X连锁的MeCP2基因座，将Ser421改变为非磷酸化的Ala残基(S421A)。与野生型(WT)小鼠相比，MeCP2 S421A敲击(KI)小鼠在强迫游泳和悬尾试验中表现出更多的静止不动。然而，急性给予丙咪嗪可降低MeCP2 WT和KI小鼠在强迫游泳中的不动能力，这表明pMeCP2的丢失不会损害对该药物的急性药理敏感性。在慢性社会失败压力后，长期服用丙咪嗪显著改善了MeCP2 WT小鼠的社会互动。相比之下，MeCP2Ki小鼠对长期给予丙咪嗪没有反应。这些数据表明，pMeCP2在对应激刺激的敏感性中扮演了新的角色，并证明了pMeCP2是慢性丙咪嗪对慢性社会失败应激诱导的抑郁样行为的影响所必需的。
Although tricyclic antidepressants rapidly activate monoaminergic neurotransmission, these drugs must be administered chronically to alleviate symptoms of depression. This observation suggests that molecular mechanisms downstream of monoamine receptor activation, which include the induction of gene transcription, underlie chronic antidepressant-induced changes in behavior. Here we show that methyl-CpG binding protein 2 (MeCP2) regulates behavioral responses to chronic antidepressant treatment. Imipramine administration induces phosphorylation of MeCP2 at Ser421 (pMeCP2) selectively in the nucleus accumbens and the lateral habenula, two brain regions important for depressive-like behaviors. To test the role of pMeCP2 in depressive-like behaviors, we utilized male mice that bear a germline mutation knocked into the X-linked Mecp2 locus that changes Ser421 to a nonphosphorylatable Ala residue (S421A). MeCP2 S421A knockin (KI) mice showed increased immobility in forced swim and tail suspension tests compared with their wildtype (WT) littermates. However immobility of both MeCP2 WT and KI mice in forced swim was reduced by acute administration of imipramine, demonstrating that loss of pMeCP2 does not impair acute pharmacological sensitivity to this drug. Following chronic social defeat stress, chronic administration of imipramine significantly improved social interaction in the MeCP2 WT mice. By contrast, the MeCP2 KI mice did not respond to chronic imipramine administration. These data suggest novel roles for pMeCP2 in the sensitivity to stressful stimuli and demonstrate that pMeCP2 is required for the effects of chronic imipramine on depressive-like behaviors induced by chronic social defeat stress.