Regulation of Protein Translation and Depression by Cortical NMDA Receptors.

描述(申请人提供)：单一、低剂量的N-甲基D-天冬氨酸受体(NMDAR)拮抗剂氯胺酮能在难治性抑郁症患者中产生快速的抗抑郁作用。这一观察结果有力地支持了皮质NMDAR功能在抑郁症中的作用，这可能导致新疾病模型和新的治疗策略的产生。虽然很明显，NMDAR拮抗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效果背后的确切机制仍不清楚。一个关键的悬而未决的问题是，抑制NMDAR信号如何促进蛋白质翻译？NMDAR是由两个GluN1亚基和两个GluN2亚基组成的杂多聚体复合体，后者由四个基因(GluN2A-D)编码。皮质NMDAR主要由GluN2A和GluN2B亚基组成。最近的数据表明，含有GluN2B的NMDARs可以通过与这个亚基相关的细胞信号机制直接抑制哺乳动物/机械靶标雷帕霉素(MTOR)介导的皮质神经元中的蛋白质翻译。基于这些数据，一个令人兴奋的假说是，解除GluN2B介导的mTOR信号抑制是产生小剂量氯胺酮治疗所观察到的快速抗抑郁效应的原因。该方案中的实验将验证这一假设，目的是提高我们对与含有GluN2B的皮质NMDAR相关的细胞信号通路的理解，并确定它们与抑郁症的关系。

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.