Department for Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hauptstrasse 5, 79104 Freiburg, Germany; Faculty of Biology, University of Freiburg, Schaenzlestrasse 1, 79104 Freiburg, Germany.
Department for Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hauptstrasse 5, 79104 Freiburg, Germany.
Neuron. 2019 Oct 23;104(2):338-352.e7. doi: 10.1016/j.neuron.2019.07.011. Epub 2019 Aug 13.
Conventional antidepressants have limited efficacy and many side effects, highlighting the need for fast-acting and specific medications. Induction of the synaptic protein Homer1a mediates the effects of different antidepressant treatments, including the rapid action of ketamine and sleep deprivation (SD). We show here that mimicking Homer1a upregulation via intravenous injection of cell-membrane-permeable TAT-Homer1a elicits rapid antidepressant effects in various tests. Similar to ketamine and SD, in vitro and in vivo application of TAT-Homer1a enhances mGlu5 signaling, resulting in increased mTOR pathway phosphorylation, and upregulates synaptic AMPA receptor expression and activity. The antidepressant action of SD and Homer1a induction depends on mGlu5 activation specifically in excitatory CaMK2a neurons and requires enhanced AMPA receptor activity, translation, and trafficking. Moreover, our data demonstrate a pronounced therapeutic potential of different TAT-fused peptides that directly modulate mGlu5 and AMPA receptor activity and thus might provide a novel strategy for rapid and effective antidepressant treatment.
传统的抗抑郁药物疗效有限，且有许多副作用，这突显了人们对起效迅速且具有特定作用的药物的需求。突触蛋白 Homer1a 的诱导介导了不同抗抑郁治疗方法的作用，包括氯胺酮的快速作用和睡眠剥夺（SD）。我们在这里表明，通过静脉注射可穿透细胞膜的 TAT-Homer1a 模拟 Homer1a 的上调，可在各种测试中引发快速的抗抑郁作用。类似于氯胺酮和 SD，TAT-Homer1a 的体外和体内应用增强了 mGlu5 信号，导致 mTOR 途径磷酸化增加，并上调了突触 AMPA 受体的表达和活性。SD 和 Homer1a 诱导的抗抑郁作用取决于兴奋性 CaMK2a 神经元中 mGlu5 的特异性激活，并且需要增强 AMPA 受体活性、翻译和运输。此外，我们的数据表明，不同的 TAT 融合肽具有明显的治疗潜力，这些肽可直接调节 mGlu5 和 AMPA 受体活性，因此可能为快速有效的抗抑郁治疗提供一种新策略。
