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迅速改变大脑中的神经传递，但需要长期服用才能影响情绪。这些观察结果表明，药物诱导的神经传递变化的下游缓慢的生物过程，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。这项建议的目标是促进对慢性抗抑郁治疗的行为反应调节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MeCP2是抗抑郁药物调节的靶标，MeCP2突变改变了小鼠对慢性抗抑郁药物治疗的行为反应。具体来说，我们发现在中枢神经系统中，包括抗抑郁药西酞普兰在内的增强5 -羟色胺和多巴胺神经传递的药物可诱导特定中枢神经系统神经元中MeCP2 Ser421位点（pMeCP2）的磷酸化。为了测试pMeCP2与抑郁样行为和抗抑郁反应的功能相关性，我们获得了一株携带种系Ser421Ala突变敲入Mecp2基因的小鼠，该突变使Mecp2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，以及这些小鼠在社会失败压力模式下对慢性抗抑郁药物治疗的反应。我们发现MeCP2敲入小鼠和它们的野生型同伴在失败后表现出相似的社交回避水平。然而，尽管慢性丙咪嗪治疗可以挽救野生型小鼠的社会互动，但这种药物治疗无法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MeCP2 Ser421位点的磷酸化至少是慢性抗抑郁治疗的一部分行为反应所必需的。这是一个全新的假设。之前没有研究检测MeCP2在抑郁样行为或抗抑郁治疗反应中的作用。我们的发现将染色质这种重要的表观遗传调节因子与慢性抗抑郁药物对大脑的作用联系起来，可能对理解抑郁样行为和抗抑郁药物反应背后的大脑过程产生重大影响。我们提出以下两个具体目标来解决我们的假设：1)分析MeCP2 KI小鼠的抑郁样行为和抗抑郁反应；2)确定MeCP2依赖性对抑郁样行为影响的神经回路。

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.