Functional significance of glycogen synthase kinase-3 regulation by serotonin

Cell Signal. 2012 Jan;24(1):265-71. doi: 10.1016/j.cellsig.2011.09.009. Epub 2011 Sep 17.

Abstract

Serotonin modulates brain physiology and behavior and has major roles in brain diseases involving abnormal mood and cognition. Enhancing brain serotonin has been found to regulate glycogen synthase Kinase-3 (GSK3), but the signaling mechanism and functional significance of this regulation remain to be determined. In this study, we tested the signaling mechanism mediating 5-HT1A receptor-regulated GSK3 in the hippocampus. Using mutant GSK3 knock-in mice, we also tested the role of GSK3 in the behavioral effects of 5-HT1A receptors and the serotonin reuptake inhibitor fluoxetine. The results showed that activation of 5-HT1A receptors by 8-hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT) increased phosphorylation of the N-terminal serine of both GSK3α and GSK3β in several areas of the hippocampus. The effect of 8-OH-DPAT was accompanied by an increase in the active phosphorylation of Akt, and was blocked by LY294002, an inhibitor of phosphoinositide 3-kinases (PI3K). Phosphorylation of GSK3β, but not GSK3α, was necessary for 5-HT1A receptors to suppress the hippocampus-associated contextual fear learning. Furthermore, acute fluoxetine treatment up-regulated both phospho-Ser21-GSK3α and phospho-Ser9-GSK3β in the hippocampus. Blocking phosphorylation of GSK3α and GSK3β diminished the anti-immobility effect of fluoxetine treatment in the forced swim test, wherein the effect of GSK3β was more prominent. These results together suggest that PI3K/Akt is a signaling mechanism mediating the GSK3-regulating effect of 5-HT1A receptors in the hippocampus, and regulation of GSK3 is an important intermediate signaling process in the behavioral functions of 5-HT1A receptors and fluoxetine.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 8-Hydroxy-2-(di-n-propylamino)tetralin / pharmacology
  • Animals
  • CA1 Region, Hippocampal / drug effects
  • CA1 Region, Hippocampal / enzymology
  • CA3 Region, Hippocampal / drug effects
  • CA3 Region, Hippocampal / enzymology
  • Chromones / pharmacology
  • Fear / drug effects
  • Fluoxetine / pharmacology
  • Freezing Reaction, Cataleptic / drug effects
  • Gene Knock-In Techniques
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / metabolism*
  • Hippocampus / drug effects
  • Hippocampus / enzymology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Morpholines / pharmacology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Selective Serotonin Reuptake Inhibitors / pharmacology
  • Serotonin / pharmacology
  • Serotonin / physiology*
  • Serotonin 5-HT1 Receptor Agonists / pharmacology
  • Signal Transduction

Substances

  • Chromones
  • Morpholines
  • Phosphoinositide-3 Kinase Inhibitors
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • Serotonin
  • 8-Hydroxy-2-(di-n-propylamino)tetralin
  • Proto-Oncogene Proteins c-akt
  • Glycogen Synthase Kinase 3