GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine.
GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine.
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DOI：
10.7554/elife.03581
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发表时间：
2014-10-23
期刊：
影响因子：
7.7
通讯作者：
Hall BJ
中科院分区：
文献类型：
--
作者：
Miller OH;Yang L;Wang CC;Hargroder EA;Zhang Y;Delpire E;Hall BJ
一个单一的，低剂量的NMDA受体拮抗剂氯胺酮产生快速的抗抑郁作用，在治疗难治性抑郁症患者。了解这背后的细胞机制将导致治疗重度抑郁症的新疗法。NMDAR是通过两个GluN 1和两个GluN 2亚基缔合形成的异多聚体复合物。我们表明，仅从主要皮质神经元中体内缺失GluN 2B，可以模拟并阻断氯胺酮对抑郁样行为和兴奋性突触传递的作用。此外，氯胺酮诱导的mTOR激活和突触蛋白合成增加在2BΔCtx小鼠中被模拟和阻断。我们在这里表明，皮质GluN 2B-含有NMDARs是唯一的激活环境谷氨酸调节兴奋性突触传递的水平。这些数据共同预测了一种新的细胞机制，解释了氯胺酮的快速抗抑郁作用。在该模型中，由皮质含GluN 2B的NMDAR感知的基础多巴胺能神经传递调节PFC中的兴奋性突触强度，决定抑郁样行为的基础水平。DOI：http://dx.doi.org/10.7554/eLife.03581.001抑郁症是全球残疾的主要原因，数亿人患有抑郁症。抑郁症治疗的“黄金标准”包括心理治疗和药物治疗的结合。不幸的是，目前的抗抑郁药物并不能帮助每个人，心理治疗的等待名单往往很长，通常都需要几个星期的定期治疗才能开始产生效果。由于患者自杀的风险往往很高，因此开发出更快速、安全有效的治疗方法至关重要。一种可能满足这些要求的物质是一种名为氯胺酮的药物。研究表明，单次低剂量的氯胺酮可以在数小时内减轻抑郁症状，这种对情绪的影响可以持续一周以上。然而，由于缺乏对氯胺酮在大脑中实际作用的了解，进展受到阻碍。神经元通过释放被称为神经递质的化学物质来相互交流，神经递质通过与其他神经元表面的受体蛋白结合来传递信息。氯胺酮等药物也与这些受体结合。氯胺酮通过阻断一种称为N-甲基D-天冬氨酸（NMDA）受体的特定受体起作用，但这是如何产生抗抑郁作用的还不完全清楚。NMDA受体实际上是由单个蛋白质亚基的组合形成的，包括一个称为GluN 2B的亚基。现在，米勒、杨等人已经创造出了新皮层神经元中缺乏含有这些GluN 2B亚基的受体的小鼠，包括前额叶皮层，这是一个涉及复杂心理过程（如决策）的大脑区域。这使得米勒，杨等人发现，当神经递质谷氨酸与含有GluN 2B的NMDA受体结合时，它限制了某些蛋白质的产生，这些蛋白质使信号更容易在神经元之间传递。过多地抑制这些蛋白质的合成可能会通过减少前额叶皮层神经元之间的交流而导致抑郁症。在皮质神经元中缺乏含GluN 2B受体的小鼠和用氯胺酮治疗的正常小鼠都表现出抑郁样行为的减少。这一证据支持了米勒，杨等人。他的理论认为，通过阻断这些NMDA受体，氯胺酮限制了它们的激活。这可以恢复蛋白质合成的正常水平，改善皮层神经元之间的交流，并减少抑郁症。了解氯胺酮如何缓解抑郁症是将其发展成为安全有效治疗方法的重要一步。还需要进一步的研究来确定导致含GluN 2B的NMDA受体过度激活的条件。DOI：http://dx.doi.org/10.7554/eLife.03581.002网站
A single, low dose of the NMDA receptor antagonist ketamine produces rapid antidepressant actions in treatment-resistant depressed patients. Understanding the cellular mechanisms underlying this will lead to new therapies for treating major depression. NMDARs are heteromultimeric complexes formed through association of two GluN1 and two GluN2 subunits. We show that in vivo deletion of GluN2B, only from principal cortical neurons, mimics and occludes ketamine's actions on depression-like behavior and excitatory synaptic transmission. Furthermore, ketamine-induced increases in mTOR activation and synaptic protein synthesis were mimicked and occluded in 2BΔCtx mice. We show here that cortical GluN2B-containing NMDARs are uniquely activated by ambient glutamate to regulate levels of excitatory synaptic transmission. Together these data predict a novel cellular mechanism that explains ketamine's rapid antidepressant actions. In this model, basal glutamatergic neurotransmission sensed by cortical GluN2B-containing NMDARs regulates excitatory synaptic strength in PFC determining basal levels of depression-like behavior. DOI: http://dx.doi.org/10.7554/eLife.03581.001 Depression is the leading cause of disability worldwide, with hundreds of millions of people living with the condition. The ‘gold standard’ for depression treatment involves a combination of psychotherapy and medication. Unfortunately, current antidepressant medications do not help everyone, waiting lists for psychotherapy are often long, and both normally take a number of weeks of regular treatment before they begin to have an effect. As patients are often at a high risk of suicide, it is crucial that treatments that act more quickly, and that are safe and effective, are developed. One substance that may fulfill these requirements is a drug called ketamine. Studies have shown that depression symptoms can be reduced within hours by a single low dose of ketamine, and this effect on mood can last for more than a week. However, progress has been hindered by a lack of knowledge about what ketamine actually does inside the brain. Neurons communicate with one another by releasing chemicals known as neurotransmitters, which transfer information by binding to receptor proteins on the surface of other neurons. Drugs such as ketamine also bind to these receptors. Ketamine works by blocking a specific receptor called the n-methyl d-aspartate (NMDA) receptor, but how this produces antidepressant effects is not fully understood. The NMDA receptor is actually formed from a combination of individual protein subunits, including one called GluN2B. Now Miller, Yang et al. have created mice that lack receptors containing these GluN2B subunits in neurons in their neocortex, including the prefrontal cortex, a brain region involved in complex mental processes such as decision-making. This allowed Miller, Yang et al. to discover that when the neurotransmitter glutamate binds to GluN2B-containing NMDA receptors, it limits the production of certain proteins that make it easier for signals to be transmitted between neurons. Suppressing the synthesis of these proteins too much may cause depressive effects by reducing communication between the neurons in the prefrontal cortex. Both mice lacking GluN2B-containing receptors in their cortical neurons and normal mice treated with ketamine showed a reduced amount of depressive-like behavior. This evidence supports Miller, Yang et al.'s theory that by blocking these NMDA receptors, ketamine restricts their activation. This restores normal levels of protein synthesis, improves communication between neurons in the cortex, and reduces depression. Understanding how ketamine works to alleviate depression is an important step towards developing it into a safe and effective treatment. Further research is also required to determine the conditions that cause overactivation of the GluN2B-containing NMDA receptors. DOI: http://dx.doi.org/10.7554/eLife.03581.002