FXR1P is a GSK3β substrate regulating mood and emotion processing

Thomas Del'Guidice, Camille Latapy, Antonio Rampino, Jivan Khlghatyan, Morgane Lemasson, Barbara Gelao, Tiziana Quarto, Giuseppe Rizzo, Annie Barbeau, Claude Lamarre, Alessandro Bertolino, Giuseppe Blasi, Jean Martin Beaulieu

Research output: Contribution to journalArticle

Abstract

Inhibition of glycogen synthase kinase 3β (GSK3β) is a shared action believed to be involved in the regulation of behavior by psychoactive drugs such as antipsychotics and mood stabilizers. However, little is known about the identity of the substrates through which GSK3β affects behavior. We identified fragile X mental retardation-related protein 1 (FXR1P), a RNA binding protein associated to genetic risk for schizophrenia, as a substrate for GSK3β. Phosphorylation of FXR1P by GSK3β is facilitated by prior phosphorylation by ERK2 and leads to its down-regulation. In contrast, behaviorally effective chronic mood stabilizer treatments in mice inhibit GSK3β and increase FXR1P levels. In line with this, overexpression of FXR1P in the mouse prefrontal cortex also leads to comparable mood-related responses. Furthermore, functional genetic polymorphisms affecting either FXR1P or GSK3β gene expression interact to regulate emotional brain responsiveness and stability in humans. These observations uncovered a GSK3β/FXR1P signaling pathway that contributes to regulating mood and emotion processing. Regulation of FXR1P by GSK3β also provides a mechanistic framework that may explain how inhibition of GSK3β can contribute to the regulation of mood by psychoactive drugs in mental illnesses such as bipolar disorder. Moreover, this pathway could potentially be implicated in other biological functions, such as inflammation and cell proliferation, in which FXR1P and GSK3 are known to play a role.

Original languageEnglish
Pages (from-to)E4610-E4619
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number33
DOIs
Publication statusPublished - Aug 18 2015

Keywords

  • Bipolar disorder
  • Emotion processing
  • FXR1P
  • Glycogen synthase kinase 3
  • Mood

ASJC Scopus subject areas

  • General

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  • Cite this

    Del'Guidice, T., Latapy, C., Rampino, A., Khlghatyan, J., Lemasson, M., Gelao, B., Quarto, T., Rizzo, G., Barbeau, A., Lamarre, C., Bertolino, A., Blasi, G., & Beaulieu, J. M. (2015). FXR1P is a GSK3β substrate regulating mood and emotion processing. Proceedings of the National Academy of Sciences of the United States of America, 112(33), E4610-E4619. https://doi.org/10.1073/pnas.1506491112