Morris Michael J, Na Elisa S, Autry Anita E, Monteggia Lisa M
Department of Psychology and Philosophy, Texas Woman's University, Denton, TX 76204, United States; Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, TX, 75390-9111, United States.
Department of Neuroscience, The University of Texas Southwestern Medical Center, Dallas, TX, 75390-9111, United States.
Neurobiol Learn Mem. 2016 Nov;135:139-145. doi: 10.1016/j.nlm.2016.08.012. Epub 2016 Aug 18.
DNA methylation has been shown to impact certain forms of synaptic and behavioral plasticity that have been implicated in the development in psychiatric disorders. DNA methylation is catalyzed by DNA methyltransferase (DNMT) enzymes that continue to be expressed in postmitotic neurons in the forebrain. Using a conditional forebrain knockout of DNMT1 or DNMT3a we assessed the role of these DNMTs in anxiety and depressive-like behavior in mice using an array of behavioral testing paradigms. Forebrain deletion of DNMT1 had anxiolytic and antidepressant-like properties as assessed by elevated plus maze, novelty suppressed feeding, forced swim, and social interaction tests. DNMT3a knockout mice, by contrast, did not exhibit significant behavioral alterations in these tests. Given the putative role of altered DNA methylation patterns in the development of schizophrenia, we also assessed DNMT1 and DNMT3a knockout mice in a prepulse inhibition task and found an enhanced prepulse inhibition of startle in DNMT1 knockouts relative to wild type mice, with no change evident in DNMT3a knockout mice. Our data suggest that DNMT1 and DNMT3a are distinctly involved in affective behavior and that DNMT1 may ultimately represent a potential target for treatment of certain affective behavioral disorders.
DNA甲基化已被证明会影响某些形式的突触可塑性和行为可塑性，这些可塑性与精神疾病的发展有关。DNA甲基化由DNA甲基转移酶（DNMT）催化，这些酶在前脑有丝分裂后的神经元中持续表达。我们使用条件性前脑敲除DNMT1或DNMT3a，通过一系列行为测试范式评估了这些DNMT在小鼠焦虑和抑郁样行为中的作用。通过高架十字迷宫、新奇抑制摄食、强迫游泳和社交互动测试评估，前脑缺失DNMT1具有抗焦虑和抗抑郁样特性。相比之下，DNMT3a基因敲除小鼠在这些测试中未表现出明显的行为改变。鉴于DNA甲基化模式改变在精神分裂症发展中的假定作用，我们还在预脉冲抑制任务中评估了DNMT1和DNMT3a基因敲除小鼠，发现与野生型小鼠相比，DNMT1基因敲除小鼠对惊吓的预脉冲抑制增强，而DNMT3a基因敲除小鼠没有明显变化。我们的数据表明，DNMT1和DNMT3a分别参与情感行为，并且DNMT1可能最终代表治疗某些情感行为障碍的潜在靶点。
