title: FXR1P is a GSK3β substrate regulating mood and emotion processing.
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.
authors.affiliation: Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Québec-City, QC, Canada G1J 2G3;
authors.forename: Thomas
authors.initials: T
authors.lastname: Del'Guidice
authors.affiliation: Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Québec-City, QC, Canada G1J 2G3;
authors.forename: Camille
authors.initials: C
authors.lastname: Latapy
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, 70100 Bari, Italy;
authors.forename: Antonio
authors.initials: A
authors.lastname: Rampino
authors.affiliation: Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Québec-City, QC, Canada G1J 2G3;
authors.forename: Jivan
authors.initials: J
authors.lastname: Khlghatyan
authors.affiliation: Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Québec-City, QC, Canada G1J 2G3;
authors.forename: Morgane
authors.initials: M
authors.lastname: Lemasson
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, 70100 Bari, Italy;
authors.forename: Barbara
authors.initials: B
authors.lastname: Gelao
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, 70100 Bari, Italy; Cognitive Brain Research Unit, Institute of Behavioral Sciences, University of Helsinki, 00014, Finland;
authors.forename: Tiziana
authors.initials: T
authors.lastname: Quarto
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, 70100 Bari, Italy;
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rizzo
authors.affiliation: Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Québec-City, QC, Canada G1J 2G3;
authors.forename: Annie
authors.initials: A
authors.lastname: Barbeau
authors.affiliation: Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Québec-City, QC, Canada G1J 2G3;
authors.forename: Claude
authors.initials: C
authors.lastname: Lamarre
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, 70100 Bari, Italy; Roche Innovation Center Basel, Hoffmann-La Roche, Ltd., 4070 Basel, Switzerland.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bertolino
authors.affiliation: Group of Psychiatric Neuroscience, Department of Basic Medical Science, Neuroscience and Sense Organs, University of Bari Aldo Moro, 70100 Bari, Italy;
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Blasi
authors.affiliation: Department of Psychiatry and Neuroscience, Faculty of Medicine, Université Laval, Québec-City, QC, Canada G1J 2G3; martin.beaulieu@crulrg.ulaval.ca.
authors.forename: Jean-Martin
authors.initials: JM
authors.lastname: Beaulieu
mesh_terms: D000328:Adult; D000339:Affect; D000818:Animals; D001522:Behavior, Animal; D004644:Emotions; D005149:Facial Expression; D005260:Female; D005786:Gene Expression Regulation; D005838:Genotype; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity; D009068:Movement; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000502:physiology; D016601:RNA-Binding Proteins / Q000502:physiology*; D014635:Valproic Acid / Q000008:administration & dosage; D055815:Young Adult
chemical_list: C096916:FXR1 protein, human; C496283:Fxr1h protein, mouse; D016601:RNA-Binding Proteins; D014635:Valproic Acid; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3
keywords: FXR1P; bipolar disorder; emotion processing; glycogen synthase kinase 3; mood