Regulation of Protein Translation and Depression by Cortical NMDA Receptors.

皮质 NMDA 受体对蛋白质翻译和抑制的调节。

• 批准号: 8635390
• 负责人: JEFFREY G TASKER
• 金额: $ 22.1万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-15 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8635390
• 关键词: AMPA Receptors; Animals; Antidepressive Agents; Behavior; Behavioral; Behavioral Assay; Biological; Cells; Chemistry; Complex; Data; Dendrites; Depressed mood; Disease model; Dose; Excision; Experimental Models; GTPase-Activating Proteins; Generations; Genes; Genetic; Glutamates; Goals; Immunofluorescence Immunologic; Intervention; Ketamine; Knock-out; Lead; Measures; Mediating; Mental Depression; Molecular; Molecular Biology; Monomeric GTP-Binding Proteins; Mus; N-Methyl-D-Aspartate Receptors; Neurons; Patients; Pharmacologic Substance; Pharmacology; Play; Prefrontal Cortex; Protein Biosynthesis; Proteins; Ras homolog enriched in brain; Receptor Signaling; Regulation; Reporter; Resistance; Role; Signal Pathway; Signal Transduction; Sirolimus; Slice; Synapses; Techniques; Testing; Translations; aspartate receptor; base; calmodulin-dependent protein kinase II; improved; novel therapeutics; public health relevance; receptor function; receptor-mediated signaling; research study; response; synaptic function; treatment-resistant depression; voltage clamp

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.

描述（由申请人提供）：单次低剂量n-甲基d-天冬氨酸受体（NMDAR）拮抗剂氯胺酮对治疗难耐的抑郁症患者产生快速抗抑郁作用。这一观察结果有力地支持了皮层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拮抗剂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的确切机制尚不清楚。一个关键的悬而未决的问题是NMDAR信号的抑制是如何促进蛋白质翻译的？NMDARs是含有两个GluN1亚基和两个GluN2亚基的异聚复合物，后者由四个基因（GluN2A-D）编码。皮质NMDARs以GluN2A和GluN2B亚基为主。最近的数据表明，含有glun2b的NMDARs可以通过与该亚基独特相关的细胞信号传导机制，直接抑制哺乳动物/机制靶雷帕霉素（mTOR）介导的皮质神经元蛋白翻译。基于这些数据，一个令人兴奋的假设是缓解glun2b介导的mTOR信号抑制是产生低剂量氯胺酮治疗中观察到的快速抗抑郁作用的原因。本提案中的实验将验证这一假设，目的是提高我们对与皮质glun2b -含NMDARs相关的细胞信号通路的理解，并确定它们与抑郁症的关系。