Regulation of Protein Translation and Depression by Cortical NMDA Receptors.

描述（由申请方提供）：单次低剂量n-甲基d-天冬氨酸受体（NMDAR）拮抗剂氯胺酮在难治性抑郁患者中产生快速抗抑郁作用。这一观察结果强烈支持皮质NMDAR功能在抑郁症中的作用，这可能导致新的疾病模型和新的治疗策略的产生。虽然很明显，NMDAR拮抗作用导致皮质神经元中蛋白质翻译的快速增加，但这些令人难以置信的作用背后的确切机制仍不清楚。一个关键的未回答的问题是如何抑制NMDAR信号促进蛋白质翻译？NMDAR是含有两个GluN 1亚基和两个GluN 2亚基的异源多聚体复合物，后者由四个基因（GluN 2A-D）编码。皮质NMDAR由GluN 2A和GluN 2B亚基主导。最近的数据表明，含有GluN 2B的NMDAR可以通过与该亚基独特相关的细胞信号传导机制直接抑制皮质神经元中雷帕霉素（mTOR）介导的蛋白质翻译的哺乳动物/机械靶标。基于这些数据，一个令人兴奋的假设是，GluN 2B介导的mTOR信号传导抑制的缓解是产生响应于低剂量氯胺酮治疗所观察到的快速抗组胺作用的原因。本提案中的实验将测试这一假设，目的是提高我们对与皮质含GluN 2B的NMDAR相关的细胞信号通路的理解，并确定其参与抑郁症。

DESCRIPTION (provided by applicant): A single, low dose of the n-methyl d-aspartate receptor (NMDAR) antagonist ketamine produces rapid anti-depressant actions in treatment-resistant depressed patients. This observation strongly supports a role for cortical NMDAR function in depression, which could lead to the generation of new disease models and novel therapeutic strategies. While it is clear that NMDAR antagonism causes a rapid increase in protein translation in cortical neurons, the exact mechanisms underlying these incredible effects remain unclear. One critical unanswered question is how does suppression of NMDAR signaling promote protein translation? NMDARs are heteromultimeric complexes containing two GluN1 subunits and two GluN2 subunits, the latter of which are encoded by four genes (GluN2A-D). Cortical NMDARs are dominated by GluN2A and GluN2B subunits. Recent data have shown that GluN2B-containing NMDARs can act to directly suppress mammalian/mechanistic target of rapamycin (mTOR)-mediated protein translation in cortical neurons, through a cellular signaling mechanism that is uniquely associated with this subunit. Based upon these data, an exciting hypothesis is that relief of GluN2B-mediated suppression of mTOR signaling is responsible for producing the rapid anti- depressant effects observed in response to low dose ketamine treatment. The experiments in this proposal will test this hypothesis with the goal of improving our understanding of the cellular signaling pathways associated with cortical GluN2B-containing NMDARs and determining their involvement in depression.