Lithium ameliorates altered glycogen synthase kinase-3 and behavior in a mouse model of fragile X syndrome.

Abstract

Fragile X syndrome (FXS), the most common form of inherited mental retardation and a genetic cause of autism, results from mutated fragile X mental retardation-1 (Fmr1). This study examined the effects on glycogen synthase kinase-3 (GSK3) of treatment with a metabotropic glutamate receptor (mGluR) antagonist, MPEP, and the GSK3 inhibitor, lithium, in C57Bl/6 Fmr1 knockout mice. Increased mGluR signaling may contribute to the pathology of FXS, and the mGluR5 antagonist MPEP increased inhibitory serine-phosphorylation of brain GSK3 selectively in Fmr1 knockout mice but not in wild-type mice. Inhibitory serine-phosphorylation of GSK3 was lower in Fmr1 knockout, than wild-type, mouse brain regions and was increased by acute or chronic lithium treatment, which also increased hippocampal brain-derived neurotrophic factor levels. Fmr1 knockout mice displayed alterations in open-field activity, elevated plus-maze, and passive avoidance, and these differences were ameliorated by chronic lithium treatment. These findings support the hypothesis that impaired inhibition of GSK3 contributes to the pathogenesis of FXS and support GSK3 as a potential therapeutic target.

• Authors: Christopher J Yuskaitis, Marjelo A Mines, Margaret K King, J David Sweatt, Courtney A Miller, Richard S Jope
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 79 Issue 4 Pg. 632-46 (Feb 15 2010) ISSN: 1873-2968 [Electronic] England
• PMID: 19799873 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Fmr1 protein, mouse
• Fragile X Mental Retardation Protein
• Glycogen Synthase Kinase 3
• Lithium Chloride

Topics

• Animals
• Avoidance Learning (drug effects, physiology)
• Disease Models, Animal
• Fragile X Mental Retardation Protein (genetics, metabolism)
• Fragile X Syndrome (drug therapy, enzymology, genetics)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, metabolism)
• Lithium Chloride (pharmacology, therapeutic use)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout