Dopaminergic abnormalities in Hdac6-deficient mice
Dopaminergic abnormalities in Hdac6-deficient mice
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DOI：
10.1016/j.neuropharm.2016.08.018
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发表时间：
2016-11-01
影响因子：
4.7
通讯作者：
Kawaguchi, Yoshiharu
中科院分区：
文献类型：
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作者：
Fukada, Masahide;Nakayama, Atsuo;Kawaguchi, Yoshiharu
组蛋白脱乙酰酶 6 (Hdac6) 是一种多功能细胞质脱乙酰酶，在大脑中含量丰富。我们之前证明，Hdac6 整体缺失会导致小鼠情绪行为异常。受影响的大脑系统及其分子基础的鉴定将为蛋白质乙酰化事件与精神疾病之间的关系带来新的见解。在这里，我们报告了 Hdac6 KO 小鼠的多巴胺能异常。已知由 D1 样和 D2 样 G 蛋白偶联多巴胺受体介导的多巴胺传递在控制运动、认知和动机过程中发挥作用，其功能障碍会导致精神疾病。我们发现 Hdac6 KO 小鼠对新环境的运动反应显着增强，但对习惯环境的反应却没有显着增强。此外，Hdac6 KO小鼠表现出对精神兴奋剂的持久敏感性，对类D2多巴胺受体激动剂（而非D1多巴胺受体激动剂）的运动反应增加，以及在多巴胺耗尽的条件下对阿扑吗啡（一种直接多巴胺激动剂）的快速运动反应。 Hdac6 蛋白在成年小鼠大脑的多巴胺能神经元及其末梢中表达，Hdac6 的缺失会增加富含多巴胺的突触体蛋白的乙酰化水平。在Hdac6 KO小鼠中，基础状态下纹状体多巴胺及其代谢物含量正常，但纹状体中D2多巴胺受体的mRNA水平降低了30%。综上所述，我们的结果提供了证据，证明 Hdac6 缺陷通过增强突触后多巴胺 D2 受体反应而导致异常的多巴胺依赖性行为。这项研究指出Hdac6和可逆乙酰化事件可能在D2多巴胺受体信号传导中发挥调节作用，从而参与多巴胺相关精神疾病（例如精神分裂症）的病理学。 (C) 2016 Elsevier Ltd. 保留所有权利。
Histone deacetylase 6 (Hdac6), a multifunctional cytoplasmic deacetylase, is abundant in brain. We previously demonstrated that global Hdac6 depletion causes aberrant emotional behaviors in mice. Identification of affected brain systems and its molecular basis will lead to new insights into relations between protein acetylation events and psychiatric disorders.Here we report the dopaminergic abnormalities in Hdac6 KO mice. The dopamine transmission mediated by D1-like and D2-like G protein-coupled dopamine receptors is known to play roles in controlling movement, cognition, and motivational processes, and its dysfunction causes psychiatric disorders. We found that Hdac6 KO mice showed significantly increased locomotor response to novel, but not to habituated environment. In addition, Hdac6 KO mice showed a long-lasting sensitivity to psychostimulants, increased locomotor response to D2-like, but not D1 dopamine receptor agonists, and rapid locomotor response to apomorphine, a direct dopamine agonist, in dopamine-depleted condition. Hdac6 protein was expressed in dopaminergic neurons and their terminals in adult mice brain, and Hdac6-depletion augmented acetylation levels of dopamine-enriched synaptosomal proteins. In Hdac6 KO mice, the striatal content of dopamine and its metabolites was normal in basal condition, but mRNA level of D2 dopamine receptor in the striatum was decreased by 30%. Taken together, our results provide evidence that Hdac6 deficiency leads to aberrant dopamine-dependent behaviors by enhancing post synaptic dopamine D2 receptor response. This study points out the possibility that Hdac6 and reversible-acetylation events play a regulatory role in D2 dopamine receptor signaling, and thus participate in the pathology of the dopamine-related psychiatric disorders such as schizophrenia. (C) 2016 Elsevier Ltd. All rights reserved.