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北京大学陆林课题组揭示快速抗抑郁治疗的新机制

来源: 中国科研用户发表    时间:2017-05-10    阅读量:

      2017年4月25日,国际学术权威刊物自然出版集团旗下子刊、神经精神病学顶尖杂志《Molecular Psychiatry》在线发表了北京大学第六医院陆林教授课题组题为“Uncoupling DAPK1 from NMDA receptor GluN2B subunit exerts rapid antidepressant-like effects”的研究论文。研究创新性提出了基于NMDA受体2B亚基的快速抗抑郁作用新理论,发现特异性抑制死亡相关蛋白激酶1(DAPK1)与GluN2B亚基的相互作用能产生快速而持久的抗抑郁效果,为研发新一代快速抗抑郁药物提供了理论依据和候选靶标。北京大学医学部的李素霞副研究员和韩盈博士以及北京大学第六医院的徐凌志博士为该论文的共同第一作者,陆林教授为通讯作者。

      抑郁症是一种高复发、高致残性的精神疾病,据世界卫生组织调查显示,全球抑郁症患者高达3.5亿以上,中国抑郁症患者已达9000万,是导致人们丧失工作和生活能力的第一疾病,也是全球每年80万人自杀的主要原因。目前临床上常用的抗抑郁药物主要针对单胺类神经递质系统,通常需要数周乃至更长时间才能发挥抗抑郁作用,且对部分患者无效或疗效不佳。因此快速抗抑郁作用神经机制的研究和快速起效抗抑郁药物的研发是目前抑郁症治疗领域亟待解决的关键问题。

      以往研究表明NMDA受体拮抗剂具有快速抗抑郁效果,尤其是氯氨酮对于难治性或有自杀倾向的抑郁症或双相情感障碍患者有良好效果,但是其快速抗抑郁作用机制目前尚不清楚。因NMDA受体不同亚基在脑内分布不同,所起作用也完全相反,含GluN2A亚基的NMDA受体在成年期主要分布于突触内,介导细胞生存和突触增强等作用;含GluN2B亚基的NMDA受体主要分布于突触外,被激活将导致兴奋性毒性,甚至细胞凋亡等。陆林教授课题组的研究发现,慢性应激导致前额叶皮层的星形胶质细胞失调、细胞外谷氨酸蓄积并溢出到突触外,激活突触外含GluN2B亚基的NMDA受体。在这个过程中细胞DAPK1的持续活化及其与GluN2B亚基的结合增加并磷酸化GluN2B亚基的丝氨酸1303位点是导致含GluN2B亚基的NMDA受体激活的关键因子。通过药理学或基因干预手段抑制DAPK1或给予特异性阻断DAPK1与GluN2B亚基结合的干扰肽均能产生快速而持久的抗抑郁作用,并且逆转前额叶皮层中慢性应激引起的分子改变和突触蛋白缺失。NMDA受体GluN2B亚基的选择性拮抗剂艾芬地尔也能产生快速抗抑郁作用,且没有成瘾性。由此,陆林教授课题组提出了突触外DAPK1与NMDA受体2B亚基相互作用介导快速抗抑郁作用的新假说,这对于快速抗抑郁新药的研发具有重要的应用价值。

 

含GluN2B亚基的NMDA受体参与快速抗抑郁作用的机制

原文链接:

Uncoupling DAPK1 from NMDA receptor GluN2B subunit exerts rapid antidepressant-like effects

原文摘要:

Several preclinical studies have reported the rapid antidepressant effects of N-methyl-D-aspartate receptor (NMDAR) antagonists, although the underlying mechanisms are still unclear. Death-associated protein kinase 1 (DAPK1) couples GluN2B subunits at extrasynaptic sites to regulate NMDAR channel conductance. In the present study, we found that chronic unpredictable stress (CUS) induced extracellular glutamate accumulation, accompanied by an increase in the DAPK1–NMDAR interaction, the high expression of DAPK1 and phosphorylated GluN2B at Ser1303, a decrease in phosphorylated DAPK1 at Ser308 and synaptic protein deficits in the rat medial prefrontal cortex (mPFC). CUS also enhanced GluN2B-mediated NMDA currents and extrasynaptic responses that were induced by bursts of high-frequency stimulation, which may be associated with the loss of astrocytes and low expression of glutamate transporter-1 (GLT-1). The blockade of GLT-1 in the mPFC was sufficient to induce depressive-like behavior and cause similar molecular changes. selecive GluN2B antagonist, DAPK1 knockdown by adeno-associated virus-mediated short-hairpin RNA or a pharmacological inhibitor, and the uncoupling of DAPK1 from the NMDAR GluN2B subunit produced rapid antidepressant-like effects and reversed CUS-induced alterations in the mPFC. The inhibition of DAPK1 and its interaction with GluN2B subunit in the mPFC also rescued CUS-induced depressive-like behavior 7 days after treatment. A selective GluN2B antagonist did not have rewarding effects in the conditioned place preference paradigm. Altogether, our findings suggest that the DAPK1 interaction with the NMDAR GluN2B subunit acts as a critical component in the pathophysiology of depression and is a potential target for new antidepressant treatments.

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