Antidepressants and Intracellular Signaling Linked to BDNF

项目摘要 在之前的资助期间，我们研究了氯胺酮的快速抗抑郁作用的机制，以及 离子型谷氨酸能N-甲基-D-天冬氨酸(NMDA)受体拮抗剂。我们展示了大脑- 衍生神经营养因子(BDNF)及其高亲和力受体TrkB是快速生长所必需的。 氯胺酮的抗抑郁作用，因为这些作用在前脑特异的BDNF基因敲除小鼠和 条件性前脑特异性TrkB基因敲除小鼠。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，导致海马区BDNF蛋白水平增加，从而 对于行为效果来说是至关重要的。氯胺酮对自发NMDA受体的阻断作用 神经传递失活真核细胞延伸因子2激酶(EEF2K)导致蛋白去磷酸化 它唯一已知的底物是真核延长因子2，从而增加了靶蛋白的翻译 成绩单，包括脑源性神经营养因子。反过来，BDNF被认为是通过诱导插入3-羟基-5-甲基-4- 突触后膜上的异恶唑丙酸(AMPA)受体，导致突触后膜 AMPA受体介导的氯胺酮对CA3-CA1区兴奋性突触后电位的影响虽然这件事 增强作用被认为是快速抗抑郁作用的细胞关联，其性质偏离了 经典的Hebbian可塑性形式，与活动后看到的动态平衡突触伸缩不谋而合 压制。这些数据为BDNF-TrkB信号调控这一新假说提供了基础 体内突触伸缩是氯胺酮快速抗抑郁作用的关键。这样做的目的是 更新是专门测试BDNF-TrkB信号在海马区的因果和指导作用 氯胺酮介导的突触伸缩和快速抗抑郁作用。总而言之，这些信息将提供 关于突触位置以及关键分子的新信息，是氯胺酮快速 抗抑郁作用。

Project Summary 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), and its high affinity receptor TrkB, are required for the rapid antidepressant effects of ketamine as these effects are lost in forebrain specific BDNF knockout mice and conditional forebrain specific TrkB knockout mice. We found the antidepressant effects of ketamine require protein translation, but not transcription, resulting in increases in BDNF protein levels in the hippocampus that are critical for the behavioral effect. Ketamine's blockade of spontaneous NMDA receptor mediated neurotransmission inactivates eukaryotic elongation factor 2 kinase (eEF2K) resulting in dephosphorylation of its only known substrate, eukaryotic elongation factor 2, thereby increasing protein translation of target transcripts, including BDNF. In turn, BDNF is postulated to act via eliciting insertion of 3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) receptors at the postsynaptic membrane, which results in potentiation of AMPA receptor-mediated CA3-CA1 field excitatory postsynaptic potentials (fEPSPs) by ketamine. While this potentiation is suggested to be a cellular correlate of rapid antidepressant effects, its properties deviate from classical Hebbian forms of plasticity and rather coincide with homeostatic synaptic scaling seen after activity suppression. These data provide the basis for the novel hypothesis that BDNF-TrkB signaling regulates synaptic scaling in vivo that is critical for the rapid antidepressant effects of ketamine. The objective of this renewal is to specifically test the causal and instructive role of BDNF-TrkB signaling in the hippocampus in ketamine-mediated synaptic scaling and rapid antidepressant effects. Collectively, this information will provide novel information on the synaptic locus, as well as key molecules, necessary for ketamine's rapid antidepressant effects.