1. CK2 regulates 5-HT4 receptor signaling and modulates depressive-like behavior
- Author
-
Heike Rebholz, Eitan Friedman, Julia Castello, Marc Flajolet, B LeFrancois, and Paul Greengard
- Subjects
Male ,0301 basic medicine ,MAPK/ERK pathway ,Indoles ,Prefrontal Cortex ,5-HT4 receptor ,Anxiety ,Biology ,Serotonergic ,Hippocampus ,Mice ,Serotonin 5-HT4 Receptor Agonists ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Downregulation and upregulation ,Animals ,Inverse agonist ,Casein Kinase II ,Neurotransmitter ,Receptor ,Molecular Biology ,Mice, Knockout ,Depressive Disorder, Major ,Sulfonamides ,Depression ,Brain ,musculoskeletal system ,Antidepressive Agents ,Corpus Striatum ,Cell biology ,Mice, Inbred C57BL ,Psychiatry and Mental health ,030104 developmental biology ,chemistry ,Knockout mouse ,Receptors, Serotonin, 5-HT4 ,Signal Transduction - Abstract
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-HT4 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-HT4 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-HT4 receptor upregulated in prefrontal cortex (PFC) but not striatum or hippocampus where CK2α is also ablated. 5-HT4 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-HT4 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-HT4 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-HT4 receptor activity and CK2 as modulator of 5-HT4 receptor levels in this brain region that regulates mood-related phenotypes.
- Published
- 2017