Department of Neurobiology, Center for Translational Neuroscience, Department of Neurology, Department of Psychiatry and Behavioral Sciences, Mouse Behavioral and Neuroendocrine Analysis Core Facility, and Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02132, Department of Pharmacology and Systems Therapeutics, Icahn School of Medicine at Mount Sinai, New York, New York 10029, and Department of Psychiatry, University of Florida College of Medicine, Gainesville, Florida 32610.
J Neurosci. 2014 Mar 26;34(13):4519-27. doi: 10.1523/JNEUROSCI.2821-13.2014.
The methyl-DNA binding protein MeCP2 is emerging as an important regulator of drug reinforcement processes. Psychostimulants induce phosphorylation of MeCP2 at Ser421; however, the functional significance of this posttranslational modification for addictive-like behaviors was unknown. Here we show that MeCP2 Ser421Ala knock-in mice display both a reduced threshold for the induction of locomotor sensitization by investigator-administered amphetamine and enhanced behavioral sensitivity to the reinforcing properties of self-administered cocaine. These behavioral differences were accompanied in the knock-in mice by changes in medium spiny neuron intrinsic excitability and nucleus accumbens gene expression typically observed in association with repeated exposure to these drugs. These data show that phosphorylation of MeCP2 at Ser421 functions to limit the circuit plasticities in the nucleus accumbens that underlie addictive-like behaviors.
甲基化-DNA 结合蛋白 MeCP2 作为一种重要的药物强化过程调节因子正在逐渐受到关注。精神兴奋剂会诱导 MeCP2 丝氨酸 421 位的磷酸化；然而，这种翻译后修饰对成瘾样行为的功能意义尚不清楚。在这里，我们发现 MeCP2 丝氨酸 421 到丙氨酸的敲入小鼠表现出对研究者给予的安非他命引起的运动敏感化的诱导阈值降低，以及对自我给予的可卡因的强化作用的行为敏感性增强。在敲入小鼠中，这些行为差异伴随着中脑腹侧被盖区中间神经元内在兴奋性和伏隔核基因表达的变化，这些变化通常与反复暴露于这些药物有关。这些数据表明，MeCP2 丝氨酸 421 位的磷酸化作用限制了伏隔核中导致成瘾样行为的回路可塑性。
