ANTIDEPRESSANTS & INTRACELLULAR SIGNALING LINKED TO BDNF

 描述（由申请方提供）：在上一个资助期，我们研究了氯胺酮（一种离子型谷氨酸能N-甲基-d-天冬氨酸（NMDA）受体拮抗剂）的快速抗抑郁活性机制。我们证明，脑源性神经营养因子（BDNF）是氯胺酮的快速抗抑郁作用所必需的，因为这些作用在前脑特异性BDNF敲除小鼠中丢失。我们发现氯胺酮的抗抑郁作用需要蛋白质翻译，而不是转录，导致BDNF蛋白的增加 海马体中对行为影响很重要的水平。最近的研究表明，阻断静息NMDA受体激活和局部树突蛋白翻译的快速增加之间有很强的因果关系。通过自发性谷氨酸释放阻断NMDA受体活化已显示使真核延伸因子2激酶失活，导致其唯一已知底物真核延伸因子2（eEF 2）去磷酸化，从而增加靶转录物的蛋白质翻译。我们发现氯胺酮导致eEF 2磷酸化减少，这通常会阻碍其磷酸化状态下的翻译，表明BDNF mRNA的翻译去抑制。此外，eEF 2激酶抑制剂在小鼠中触发快速抗抑郁样作用，氯胺酮在eEF 2激酶缺失小鼠中不引起抗抑郁作用。这些数据为新的假设提供了基础，即氯胺酮通过阻断休息时的NMDA受体，抑制eEF 2的磷酸化并增强随后的BDNF表达，这是氯胺酮介导的抗抑郁疗效的关键决定因素。更新的目的是描述海马中BDNF-TrkB信号在氯胺酮介导的抗抑郁作用中的作用，以及eEF 2激酶如何作为NMDA受体活性和BDNF调节之间的转换器。总的来说，这些信息将提供关于突触位点的新信息， 以及氯胺酮快速抗抑郁作用的关键分子。

 DESCRIPTION (provided by applicant): In the previous funding period we investigated the mechanism of rapid antidepressant activity of ketamine, an ionotropic glutamatergic n-methyl-d-aspartate (NMDA) receptor antagonist. We demonstrated that Brain-derived neurotrophic factor (BDNF) is required for the fast acting antidepressant effects of ketamine as these effects are lost in forebrain specific BDNF knockout mice. We found that the antidepressant effects of ketamine require protein translation, but not transcription, resulting in increases in BDNF protein levels in the hippocampus that are important for the behavioral effect. Recent work has suggested a strong causal link between blockade of resting NMDA receptor activation and rapid increases in local dendritic protein translation. Blockade of NMDA receptor activation by spontaneous glutamate release has been shown to inactive eukaryotic elongation factor 2 kinase resulting in dephosphorylation of its only known substrate, eukaryotic elongation factor 2 (eEF2), thereby increasing protein translation of target transcripts. We showed that ketamine causes a decrease in phosphorylation of eEF2, which normally impedes translation in its phosphorylated state, suggesting translational de-repression of BDNF mRNA. Moreover, inhibitors of eEF2 kinase trigger a rapid antidepressant-like effect in mice and ketamine does not elicit an antidepressant effect in eEF2 kinase null mice. These data provide the basis for the novel hypothesis that ketamine, by blocking NMDA receptors at rest, inhibits the phosphorylation of eEF2 and augments subsequent expression of BDNF, critical determinants of ketamine-mediated antidepressant efficacy. The objective of this renewal is to delineate the role of BDNF-TrkB signaling in the hippocampus in ketamine-mediated antidepressant effects, as well as how eEF2 kinase acts as a transducer between NMDA receptor activity and BDNF regulation. Collectively, this information will provide novel information on the synaptic locus, as well as the key molecules, necessary for ketamine's rapid antidepressant effects.