ANTIDEPRESSANTS & INTRACELLULAR SIGNALING LINKED TO BDNF

 描述(申请人提供)：在之前的资助期间，我们研究了氯胺酮的快速抗抑郁作用机制，氯胺酮是一种离子型谷氨酸能N-甲基-D-天冬氨酸(NMDA)受体拮抗剂。我们证明脑源性神经营养因子(BDNF)是氯胺酮快速抗抑郁作用所必需的，因为这些作用在前脑特异的BDNF基因敲除小鼠中消失了。我们发现，氯胺酮的抗抑郁作用需要蛋白质的翻译，而不是转录，导致BDNF蛋白的增加 海马体中对行为效果很重要的水平。最近的工作表明，阻断静止的NMDA受体激活与局部树突状蛋白翻译的快速增加之间存在强烈的因果联系。研究表明，通过自发释放谷氨酸来阻断NMDA受体的激活，可以使真核延伸因子2激酶失活，导致其唯一已知的底物真核延伸因子2(EEF2)去磷酸化，从而增加目标转录物的蛋白质翻译。我们发现，氯胺酮导致eEF2磷酸化水平的降低，这通常会阻碍处于磷酸化状态的翻译，这表明BDNF mRNA的翻译下调。此外，eEF2激酶的抑制剂在小鼠中引发快速的抗抑郁药样作用，而氯胺酮不能在eEF2激酶缺失的小鼠中引起抗抑郁作用。这些数据为新的假说提供了基础，即氯胺酮通过阻断静息状态下的NMDA受体，抑制eEF2的磷酸化，并增强随后BDNF的表达，这是氯胺酮介导的抗抑郁疗效的关键决定因素。这一更新的目的是描述海马区BDNF-TrkB信号在氯胺酮介导的抗抑郁效应中的作用，以及eEF2激酶如何在NMDA受体活性和BDNF调节之间发挥转导作用。总而言之，这些信息将提供有关突触轨迹的新信息，如 以及氯胺酮快速抗抑郁作用所必需的关键分子。

 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.