Enhanced mGlu5 Signaling in Excitatory Neurons Promotes Rapid Antidepressant Effects via AMPA Receptor Activation
Enhanced mGlu5 Signaling in Excitatory Neurons Promotes Rapid Antidepressant Effects via AMPA Receptor Activation
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DOI：
10.1016/j.neuron.2019.07.011
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发表时间：
2019-10-23
期刊：
影响因子：
16.2
通讯作者：
Serchov, Tsvetan
中科院分区：
文献类型：
--
作者：
Holz, Amrei;Muelsch, Felix;Serchov, Tsvetan
传统的抗抑郁药疗效有限，而且有许多副作用，因此需要快速起效的特异性药物。突触蛋白Homer 1a的诱导介导了不同抗抑郁治疗的效果，包括氯胺酮和睡眠剥夺（SD）的快速作用。我们在这里表明，通过静脉注射细胞膜可渗透的TAT-Homer 1a模拟Homer 1a上调在各种测试中产生快速的抗抑郁作用。与氯胺酮和SD类似，TAT-Homer 1a的体外和体内应用增强mGlu 5信号传导，导致mTOR通路磷酸化增加，并上调突触AMPA受体表达和活性。SD和Homer 1a诱导的抗抑郁作用依赖于兴奋性CaMK 2a神经元中特异性的mGlu 5激活，并且需要增强的AMPA受体活性、翻译和运输。此外，我们的数据表明，直接调节mGlu 5和AMPA受体活性的不同TAT融合肽具有明显的治疗潜力，因此可能提供一种快速有效的抗抑郁治疗的新策略。
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.