Elucidating the functions of brain GSK3α: Possible synergy with GSK3β upregulation and reversal by antidepressant treatment in a mouse model of depressive-like behaviour

Behav Brain Res. 2017 Sep 29;335:122-127. doi: 10.1016/j.bbr.2017.08.018. Epub 2017 Aug 10.

Abstract

Glycogen synthase kinase 3 (GSK3) has been linked to the mechanisms of stress, mood regulation, and the effects of antidepressants. The functions of the GSK3β isoform have been extensively investigated, but little is known about the α-isoform, although they may functionally related. In a recently established modified swim test with a third delayed swim exposure, brain GSK3β mRNA expression positively correlated with floating behaviour on the third test. A two-week-long pretreatment regime with imipramine (7.5mg/kg/day) or thiamine (200mg/kg/day), which is known to have antidepressant properties, reduced the GSK3β over-expression and decreased floating behaviour on Day 5. GSK3α mRNA levels were measured in the hippocampus and prefrontal cortex on Days 1, 2 and 5. GSK3α expression was decreased in the prefrontal cortex on Day 2 and increased on Day 5. In this model, GSK3α mRNA changes were prevented by imipramine or thiamine treatment. There was a significant correlation between the expression of the two isoforms in the prefrontal cortex on Day 2 in untreated group. These results provide the first evidence for the potential involvement of GSK3α in depressive-like behaviours and as a target of anti-depressant therapy. Furthermore, the correlations suggest some cross-talk may exist between the two GSK3 isoforms.

Keywords: Depression; GSK3α; Imipramine; Mice; Prefrontal cortex; Thiamine.

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Brain / drug effects
  • Brain / enzymology*
  • Brain / metabolism
  • Brain / pathology
  • Depression / drug therapy*
  • Depression / enzymology*
  • Depression / metabolism
  • Depression / pathology
  • Disease Models, Animal
  • Glycogen Synthase Kinase 3 / metabolism*
  • Glycogen Synthase Kinase 3 beta / metabolism*
  • Imipramine / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphorylation
  • Protein Isoforms
  • Signal Transduction / drug effects
  • Thiamine / pharmacology
  • Up-Regulation

Substances

  • Antidepressive Agents
  • Protein Isoforms
  • Glycogen Synthase Kinase 3 beta
  • Glycogen Synthase Kinase 3
  • glycogen synthase kinase 3 alpha
  • Imipramine
  • Thiamine