Aoyama Yuki, Mouri Akihiro, Toriumi Kazuya, Koseki Takenao, Narusawa Shiho, Ikawa Natsumi, Mamiya Takayoshi, Nagai Taku, Yamada Kiyofumi, Nabeshima Toshitaka
Department of Chemical Pharmacology, Graduate School of Pharmaceutical Sciences, Meijo University, Nagoya, Japan.
The Academic Frontier Project for Private Universities, Comparative Cognitive Science Institutes, Meijo University, Nagoya, Japan.
Int J Neuropsychopharmacol. 2014 May;17(5):723-37. doi: 10.1017/S1461145713001466. Epub 2013 Dec 17.
Accumulating evidence suggests that dysregulation of histone modification is involved in the pathogenesis and/or pathophysiology of psychiatric disorders. However, the abnormalities in histone modification in the animal model of schizophrenia and the efficacy of antipsychotics for such abnormalities remain unclear. Here, we investigated the involvement of histone modification in phencyclidine-induced behavioral abnormalities and the effects of antipsychotics on these abnormalities. After repeated phencyclidine (10 mg/kg) treatment for 14 consecutive days, mice were treated with antipsychotics (clozapine or haloperidol) or the histone deacetylase inhibitor sodium butyrate for 7 d. Repeated phencyclidine treatments induced memory impairment and social deficit in the mice. The acetylation of histone H3 at lysine 9 residues decreased in the prefrontal cortex with phencyclidine treatment, whereas the expression level of histone deacetylase 5 increased. In addition, the phosphorylation of Ca²⁺/calmodulin-dependent protein kinase II in the nucleus decreased in the prefrontal cortex of phencyclidine-treated mice. These behavioral and epigenetic changes in phencyclidine-treated mice were attenuated by clozapine and sodium butyrate but not by haloperidol. The dopamine D1 receptor antagonist SCH-23390 blocked the ameliorating effects of clozapine but not of sodium butyrate. Furthermore, clozapine and sodium butyrate attenuated the decrease in expression level of GABAergic system-related genes in the prefrontal cortex of phencyclidine-treated mice. These findings suggest that the antipsychotic effect of clozapine develops, at least in part, through epigenetic modification by activation of the dopamine D1 receptor in the prefrontal cortex.
越来越多的证据表明，组蛋白修饰失调与精神疾病的发病机制和/或病理生理学有关。然而，精神分裂症动物模型中组蛋白修饰的异常以及抗精神病药物对这些异常的疗效仍不清楚。在此，我们研究了组蛋白修饰与苯环己哌啶诱导的行为异常的关系以及抗精神病药物对这些异常的影响。连续14天重复给予苯环己哌啶（10mg/kg）后，小鼠接受抗精神病药物（氯氮平或氟哌啶醇）或组蛋白去乙酰化酶抑制剂丁酸钠治疗7天。重复给予苯环己哌啶会导致小鼠出现记忆障碍和社交缺陷。苯环己哌啶处理后，前额叶皮质中赖氨酸9残基处的组蛋白H3乙酰化减少，而组蛋白去乙酰化酶5的表达水平增加。此外，苯环己哌啶处理的小鼠前额叶皮质中细胞核内Ca²⁺/钙调蛋白依赖性蛋白激酶II的磷酸化减少。氯氮平和丁酸钠可减轻苯环己哌啶处理小鼠的这些行为和表观遗传变化，而氟哌啶醇则不能。多巴胺D1受体拮抗剂SCH-23390可阻断氯氮平的改善作用，但不能阻断丁酸钠的作用。此外，氯氮平和丁酸钠可减轻苯环己哌啶处理小鼠前额叶皮质中γ-氨基丁酸能系统相关基因表达水平的降低。这些发现表明，氯氮平的抗精神病作用至少部分是通过激活前额叶皮质中的多巴胺D1受体进行表观遗传修饰而产生的。
