In vivo regulation of glycogen synthase kinase-3β (GSK3β) by serotonergic activity in mouse brain

Xiaohua Li, Wawa Zhu, Myoung Sun Roh, Ari B. Friedman, Kelley Rosborough, Richard S. Jope

Research output: Contribution to journalArticlepeer-review

261 Scopus citations

Abstract

The goal of this study was to determine if serotonergic activity, which is impaired in depression, regulates the phosphorylation of glycogen synthase kinase-3β (GSK3β) in mouse brain in vivo. GSK3β is inhibited by phosphorylation on serine-9 and is a target of the mood stabilizer lithium. Following administration to mice of d-fenfluramine to stimulate serotonin (5HT) release and reduce its reuptake, and clorgyline to inhibit 5HT catabolism, levels of phospho-Ser9-GSK3β were 300-400% of control levels in the prefrontal cortex, hippocampus, and striatum. Treatment with monoamine reuptake inhibitors fluoxetine and imipramine also increased the level of phospho-Ser9-GSK3β. Using receptor selective agonists and antagonists, 5HT1A receptors were found to mediate increases, and 5HT2 receptors decreases, in phospho-Ser9-GSK3β levels. This indicates that serotonergic regulation of the phosphorylation of GSK3β is achieved by a balance between the opposing actions of these 5HT receptor subtypes. These findings demonstrate for the first time that serotonergic activity regulates the phosphorylation of GSK3β and show that this regulation occurs in mammalian brain in vivo. These results raise the possibility that impaired inhibitory control of GSK3β may occur in conditions where serotonergic activity is dysregulated, such as in mood disorders.

Original languageEnglish (US)
Pages (from-to)1426-1431
Number of pages6
JournalNeuropsychopharmacology
Volume29
Issue number8
DOIs
StatePublished - Aug 2004

Keywords

  • 5HT1A receptor
  • 5HT2 receptor
  • Depression
  • Glycogen synthase kinase-3β
  • Serotonin

ASJC Scopus subject areas

  • Pharmacology

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