Antidepressants and Intracellular Signaling Linked to BDNF

项目摘要 在上一个资助期，我们研究了氯胺酮快速抗抑郁活性的机制， 离子型谷氨酸能N-甲基-D-天冬氨酸（NMDA）受体拮抗剂。我们证明了大脑- 衍生的神经营养因子（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性BDNF敲除小鼠中丧失， 条件性前脑特异性TrkB敲除小鼠。我们发现克他命的抗抑郁作用需要 蛋白质翻译，而不是转录，导致海马中BDNF蛋白质水平的增加， 对行为效应至关重要。氯胺酮对自发性NMDA受体介导的 神经传递失活真核细胞延伸因子2激酶（eEF 2K），导致 其唯一已知的底物，真核延伸因子2，从而增加靶蛋白的翻译 包括BDNF在内的转录本。反过来，BDNF被假定为通过引发3-羟基-5-甲基-4-甲基-N- 异恶唑丙酸（AMPA）受体在突触后膜，这导致增强的 AMPA受体介导的CA 3-CA 1场兴奋性突触后电位（fEPSP）氯胺酮。虽然这 增强被认为是快速抗抑郁作用的细胞相关性，其性质偏离 经典的赫布形式的可塑性，而符合稳态突触缩放后看到的活动 镇压这些数据为BDNF-TrkB信号转导调节细胞凋亡的新假说提供了基础。 体内突触缩放对于氯胺酮的快速抗抑郁作用至关重要。的目的 更新的目的是专门测试海马中BDNF-TrkB信号传导的因果和指导作用， 氯胺酮介导的突触缩放和快速抗抑郁作用。总的来说，这些信息将提供 新的信息的突触位点，以及关键分子，所需的氯胺酮的快速 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.