Department of Physiology, Pharmacology and Neuroscience, CUNY School of Medicine, New York, NY, USA.
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY, USA.
Mol Psychiatry. 2018 Apr;23(4):872-882. doi: 10.1038/mp.2017.240. Epub 2017 Nov 21.
The serotonergic neurotransmitter system has been widely implicated in the pathophysiology of mood-related disorders such as anxiety and major depressive disorder (MDD). The onset of therapeutic efficacy of traditional antidepressants is delayed by several weeks. The 5-HT receptor has emerged as a new therapeutic target since agonists of this receptor induce rapid antidepressant-like responses in rodents. Here we show that the 5-HT receptor is regulated by CK2, at transcriptional and post-transcriptional levels. We present evidence, in two different CK2α knockout mouse lines, that this regulation is region-specific, with the 5-HT receptor upregulated in prefrontal cortex (PFC) but not striatum or hippocampus where CK2α is also ablated. 5-HT receptor signaling is enhanced in vitro, as evidenced by enhanced cAMP production or receptor plasma membrane localization in the presence of CK2 inhibitor or shRNA targeting CK2α. In vivo, 5-HT receptor signaling is also upregulated since ERK activation is elevated and sensitive to the inverse agonist, GR113808 in the PFC of CK2α KO mice. Behaviorally, KO mice as well as mice with AAV-mediated deletion of CK2α in the PFC show a robust 'anti-depressed-like' phenotype and display an enhanced response to antidepressant treatment when tested in paradigms for mood and anxiety. Importantly, it is sufficient to overexpress the 5-HT receptor in the mPFC to generate mice with a similar 'anti-depressed-like' phenotype. Our findings identify the mPFC as the region that mediates the effect of enhanced 5-HT receptor activity and CK2 as modulator of 5-HT4 receptor levels in this brain region that regulates mood-related phenotypes.
5-羟色胺能神经递质系统广泛参与与情绪相关的疾病（如焦虑和重度抑郁症（MDD））的病理生理学。传统抗抑郁药的治疗效果起效缓慢，需要数周时间。由于该受体的激动剂可在啮齿动物中诱导快速的抗抑郁样反应，因此 5-羟色胺受体已成为新的治疗靶点。在这里，我们显示 5-羟色胺受体受 CK2 调控，表现在转录和转录后水平。我们提出了证据，在两种不同的 CK2α 敲除小鼠品系中，这种调控是具有区域特异性的，5-羟色胺受体在前额叶皮层（PFC）上调，但在纹状体或海马体中没有上调，而 CK2α 也被消融。在存在 CK2 抑制剂或靶向 CK2α 的 shRNA 的情况下，体外 5-羟色胺受体信号增强，表现在 cAMP 产生增加或受体质膜定位增强。在体内，5-羟色胺受体信号也上调，因为 ERK 激活增加，并且对 CK2α 敲除小鼠 PFC 中的反向激动剂 GR113808 敏感。行为上，CK2α 敲除小鼠以及在 PFC 中通过 AAV 介导的 CK2α 缺失的小鼠表现出强烈的“抗抑郁样”表型，并且在情绪和焦虑的范式中测试时对抗抑郁治疗的反应增强。重要的是，在 mPFC 中过表达 5-羟色胺受体足以产生具有类似“抗抑郁样”表型的小鼠。我们的研究结果确定了 mPFC 是介导增强的 5-羟色胺受体活性的区域，并且 CK2 是调节与情绪相关表型的该脑区 5-羟色胺 4 受体水平的调节剂。
