Epigenetic gene-regulation abnormalities have been implicated in various neuropsychiatric disorders including schizophrenia and depression, as well as in the regulation of mood and anxiety. In addition, epigenetic mechanisms are involved in the actions of psychiatric drugs. Current anxiolytic drugs have significant shortcomings, and development of new medications is warranted. Two proteins, G9a (also known as EHMT2 or KMT1C) and GLP (G9a-like protein, also known as EHMT1 or KMT1D), which methylate lysine 9 of histone H3 (H3K9), could be promising anxiolytic targets. Postnatal genetic knock-out of G9a reduces anxiety-related behavior, consistent with the reduction of G9a levels by some medications used to treat anxiety (amitriptyline, imipramine and paroxetine). Conversely, there is increased anxiety-like behavior in mice with GLP haplodeficiency. We sought to determine whether two pharmacological inhibitors of G9a/GLP, UNC0642 and A-366, would have similar effects to genetic G9a/GLP insufficiency. We found that G9a/GLP inhibition with either compound reduced anxiety-like behaviors when administered to adult mice, in conjunction with decreased H3K9 methylation in the brain. In contrast, exposure to these compounds from embryonic day 9.5 (E9.5) until birth increased anxiety-like behaviors and decreased social interaction in adulthood, while H3K9 methylation was at normal levels in the brains of the adult mice. These findings reinforce genetic evidence that G9a/GLP has different effects on anxiety-like behavior at different stages of brain development, and suggest that targeting this histone methyltransferase pathway could be useful for developing new anxiolytic drugs. These data also suggest that antidepressant exposure in utero could have negative effects in adulthood, and further investigation of these effects is warranted.

中文翻译：

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G9a / GLP组蛋白甲基转移酶复合物的抑制作用可调节小鼠的焦虑相关行为。

表观遗传基因调节异常与各种神经精神疾病有关，包括精神分裂症和抑郁症，以及情绪和焦虑的调节。此外，表观遗传机制也参与了精神药物的作用。当前的抗焦虑药具有明显的缺点，并且有必要开发新的药物。两种蛋白，G9a（也称为EHMT2或KMT1C）和GLP（G9a样蛋白，也称为EHMT1或KMT1D），可以将组蛋白H3（H3K9）的赖氨酸9甲基化，有望成为抗焦虑的靶标。产后基因敲除G9a可以减少与焦虑相关的行为，这与某些用于治疗焦虑的药物（阿米替林，丙咪嗪和帕罗西汀）降低G9a水平相一致。相反，患有GLP单倍体缺乏症的小鼠的焦虑样行为增加。我们试图确定两种G9a / GLP药理抑制剂UNC0642和A-366是否会与遗传性G9a / GLP功能不足有关。我们发现，对成年小鼠给药后，用这两种化合物抑制G9a / GLP均可减少焦虑样行为，并降低大脑中的H3K9甲基化。相比之下，从胚胎第9.5天（E9.5）直到出生，接触这些化合物会增加成年后的焦虑样行为并减少社交互动，而成年小鼠的大脑中H3K9甲基化水平处于正常水平。这些发现加强了遗传证据，表明G9a / GLP对大脑发育不同阶段的焦虑样行为具有不同的影响，并表明靶向此组蛋白甲基转移酶途径可能对开发新的抗焦虑药有用。