Regulation of response to chronic antidepressant treatment by MeCP2

描述（由申请人提供）：目前大多数可用的抗抑郁药物都会迅速改变大脑的神经传递，但需要长期给药才能影响情绪。这些观察结果表明，药物诱导的神经传递变化下游的缓慢生物学过程（被认为包括基因转录的变化）可能是对这些抗抑郁药物的行为反应所必需的。该提案的目标是促进对调节慢性抗抑郁治疗的行为反应的基本大脑机制的理解。我们已经发现甲基DNA结合染色质调节蛋白MeCP 2是抗抑郁药调节的靶点，并且MeCP 2的突变改变了小鼠对慢性抗抑郁药治疗的行为反应。具体地说，我们发现，管理的药物，增强血清素和多巴胺的神经传递中枢神经系统，包括抗抑郁药西酞普兰，诱导磷酸化的MeCP 2在Ser 421（pMeCP 2）在选定的中枢神经系统神经元。为了测试pMeCP 2与抑郁样行为和抗抑郁反应的功能相关性，我们获得了一种小鼠品系，该品系携带种系Ser 421 Ala突变，该突变敲入Mecp 2基因，使得MeCP 2蛋白在该位点不可磷酸化。我们已经测试了这种突变对抑郁样行为的影响，以及在社交失败压力范例中这些小鼠对慢性抗抑郁治疗的反应。我们发现MeCP 2基因敲入小鼠和它们的野生型同窝出生的小鼠在失败后表现出相似的社交回避水平。然而，尽管长期丙咪嗪治疗挽救了野生型小鼠的社会互动，但这种药物治疗未能改善敲入小鼠的社会回避。基于这些和其他初步数据，我们假设MeCP 2在Ser 421处的磷酸化是慢性抗抑郁药治疗的至少一部分行为反应所必需的。这是一个全新的假设。之前没有研究检查过MeCP 2在抑郁样行为或抗抑郁治疗反应中的作用。我们的研究结果可能会对理解抑郁样行为和抗抑郁药反应的大脑过程产生重大影响，将这种重要的染色质表观遗传调节因子与慢性抗抑郁药给药对大脑的作用联系起来。我们提出以下两个具体目标来解决我们的假设：1）分析MeCP 2 KI小鼠的抑郁样行为和抗抑郁反应; 2）确定MeCP 2依赖性对抑郁样行为影响的神经回路。 公共卫生相关性：抑郁症和相关的情绪障碍影响着数百万美国人，每年在医疗、生产力损失和过早死亡方面花费我们的社会数百亿美元。该提案将解决表观遗传转录调节因子MeCP 2在抗抑郁药物的慢性作用中的作用。这项研究有可能揭示调节抑郁样行为和抗抑郁治疗反应的潜在大脑机制的新见解。

DESCRIPTION (provided by applicant): Most currently available antidepressant drugs rapidly alter neurotransmission in the brain yet require chronic administration to affect mood. These observations suggest that slow biological processes downstream of drug- induced changes in neurotransmission, which are thought to include changes in gene transcription, are likely to be required for the behavioral response to these antidepressant drugs. The goal of this proposal is to advance understanding of the basic brain mechanisms that regulate behavioral responses to chronic antidepressant treatment. We have discovered that the methyl-DNA binding chromatin regulatory protein MeCP2 is a target of regulation by antidepressants, and that mutations in MeCP2 alter behavioral responses to chronic antidepressant treatment in mice. Specifically we find that administration of drugs that enhance serotonin and dopamine neurotransmission in the CNS, including the antidepressant citalopram, induces phosphorylation of MeCP2 at Ser421 (pMeCP2) in selected CNS neurons. To test the functional relevance of pMeCP2 for depressive-like behaviors and antidepressant responses we obtained a strain of mice that bear a germline Ser421Ala mutation knocked into the Mecp2 gene that renders MeCP2 protein nonphosphorylatable at this site. We have tested the consequence of this mutation on depressive-like behaviors and response to chronic antidepressant treatment in these mice in the social defeat stress paradigm. We find that both MeCP2 knockin mice and their wildtype littermates show similar levels of social avoidance following defeat. However whereas chronic imipramine treatment rescues social interaction in the wildtype mice, this drug treatment fails to ameliorate social avoidance in the knockin mice. On the basis of these and other preliminary data we hypothesize that phosphorylation of MeCP2 at Ser421 is required for at least a subset of behavioral responses to chronic antidepressant treatment. This is a completely novel hypothesis. No prior studies have examined a role for MeCP2 in depressive-like behaviors or response to antidepressant treatment. Our findings could have a substantial impact on the understanding of brain processes that underlie depressive-like behaviors and response to antidepressants by linking this important epigenetic regulator of chromatin to the actions of chronic antidepressant administration on the brain. We propose to address our hypothesis with the following two specific aims: 1) To analyze depressive-like behaviors and antidepressant responses in MeCP2 KI mice and 2) To identify neural circuits that underlie MeCP2-dependent effects on depressive-like behaviors. PUBLIC HEALTH RELEVANCE: Depression and related mood disorders affect millions of Americans and cost our society tens of billions of dollars each year in medical treatments, lost productivity, and premature mortality. This proposal will address the role of the epigenetic transcriptional regulator MeCP2 in the chronic actions of antidepressant drugs. This study has the potential to reveal novel insights into the underlying brain mechanisms that regulate depressive- like behaviors and response to antidepressant treatment.