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

Christopher J. Yuskaitis, Marjelo A. Mines, Margaret K. King, J. David Sweatt, Courtney A. Miller, Richard S Jope

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)632-646
Number of pages15
JournalBiochemical Pharmacology
Volume79
Issue number4
DOIs
StatePublished - Feb 15 2010
Externally publishedYes

Fingerprint

Glycogen Synthase Kinase 3
Fragile X Syndrome
Lithium
Intellectual Disability
Knockout Mice
Phosphorylation
Metabotropic Glutamate Receptors
Serine
Brain
Excitatory Amino Acid Antagonists
Brain-Derived Neurotrophic Factor
Pathology
Autistic Disorder

Keywords

  • Autism
  • FMR1
  • Glycogen synthase kinase-3
  • Lithium
  • MPEP

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

Cite this

Lithium ameliorates altered glycogen synthase kinase-3 and behavior in a mouse model of Fragile X syndrome. / Yuskaitis, Christopher J.; Mines, Marjelo A.; King, Margaret K.; Sweatt, J. David; Miller, Courtney A.; Jope, Richard S.

In: Biochemical Pharmacology, Vol. 79, No. 4, 15.02.2010, p. 632-646.

Research output: Contribution to journalArticle

Yuskaitis, Christopher J. ; Mines, Marjelo A. ; King, Margaret K. ; Sweatt, J. David ; Miller, Courtney A. ; Jope, Richard S. / Lithium ameliorates altered glycogen synthase kinase-3 and behavior in a mouse model of Fragile X syndrome. In: Biochemical Pharmacology. 2010 ; Vol. 79, No. 4. pp. 632-646.
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