Antidepressants and Intracellular Signaling Linked to BDNF

摘要 脑源性神经营养因子(BDNF)是大脑中最常见的神经营养因子，通过其高水平的作用而发挥作用。 亲和力TrkB受体它增强多种类型的中枢神经元的存活，并与几种 大脑中神经可塑性的各种形式。最近的研究表明，海马区内源性BDNF可能 参与调节抗抑郁药物的反应，在小鼠的抑郁模型中。一项相当令人惊讶的发现 抑郁症的领域已经证明，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，对抑郁症有快速持久的抗抑郁作用 个人。我们已经开始研究氯胺酮抗抑郁作用的机制， 特别是内源性脑源性神经营养因子在海马区的潜在参与。在初步实验中， 我们发现，NMDA受体拮抗剂氯胺酮、MK801或CPP能产生快速有效的抗抑郁药 对小鼠抑郁模型的行为影响。氯胺酮的快速抗抑郁作用是通过 这是一种BDNF依赖的方式，因为这些效应在前脑特异的BDNF基因敲除小鼠中消失。我们的 研究结果还表明，氯胺酮的抗抑郁作用需要蛋白质翻译，但不需要 转录，导致BDNF蛋白水平的增加，这对行为效应是重要的。近期 研究表明，阻断静息中的NMDA受体激活与快速 增加局部树突状蛋白的翻译。与最近的体外工作一致，我们发现氯胺酮 导致真核细胞延伸因子2(EEF2)的磷酸化减少，这通常会阻碍 翻译处于磷酸化状态，提示BDNF mRNA的翻译下调。重要的是，我们 提供初步证据表明，eEF2激酶抑制剂(也称为CaMKIII)通常 磷酸化的eEF2在小鼠的抑郁模型中触发了一种快速作用的抗抑郁药样效应。这些 研究结果提示NMDA抑制树突状细胞的翻译抑制与行为和临床相关 感受器。这笔赠款的目的是将对翻译抑制的调节与 抗抑郁药。总的来说，这些研究承诺提供关于以下方面的根本新颖的信息 海马区内源性BDNF如何参与氯胺酮的快速抗抑郁反应 并为开发作用更快的抗抑郁药提供了新的线索。

ABSTRACT Brain-derived neurotrophic factor (BDNF) is the most prevalent neurotrophin in brain; via actions on its high affinity trkB receptor it enhances the survival of many types of central neurons and is implicated in several forms of neural plasticity in the brain. Recent work suggests that endogenous BDNF in the hippocampus may be involved in mediating antidepressant responses, in depression models in mice. A rather surprising finding in the field of depression has been the demonstration that ketamine, an ionotropic glutamatergic n-methyl-daspartate (NMDA) receptor antagonist, has rapid and long-lasting antidepressant effects in depressed individuals. We have started to investigate the mechanisms of the antidepressant activity of ketamine, specifically the potential involvement of endogenous BDNF in the hippocampus. In preliminary experiments, we find that the NMDA receptor antagonists, ketamine, MK801 or CPP, produce fast-acting antidepressant behavioral effects in depression models in mice. The fast acting antidepressant effects of ketamine occurs via a BDNF dependent manner because these effects are lost in forebrain specific BDNF knockout mice. Our findings also suggest that the antidepressant effects of ketamine require protein translation, but not transcription, resulting in increases in BDNF protein levels 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. In agreement with recent in vitro work, we find that ketamine causes a decrease in phosphorylation of eukaryotic elongation factor 2 (eEF2), which normally impedes translation in its phosphorylated state, suggesting translational de-repression of BDNF mRNA. Importantly, we provide preliminary evidence that inhibitors of the eEF2 kinase (also called CaMKIII) that normally phosphorylates eEF2 trigger a fast-acting antidepressant-like effect in depression models in mice. These findings suggest a behavioral and clinically relevant correlate of dendritic translational de-repression by NMDA receptors. The objective of this grant is to link the regulation of translational repression to the effects of antidepressants. Collectively, these studies promise to provide fundamentally novel information concerning how endogenous BDNF in the hippocampus is involved in the fast acting antidepressant response of ketamine and offer new leads toward the development of faster acting antidepressants.