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FXR1P is a GSK3? substrate regulating mood and emotion processing.

ABSTRACT: Inhibition of glycogen synthase kinase 3? (GSK3?) 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 GSK3? 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 GSK3?. Phosphorylation of FXR1P by GSK3? is facilitated by prior phosphorylation by ERK2 and leads to its down-regulation. In contrast, behaviorally effective chronic mood stabilizer treatments in mice inhibit GSK3? 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 GSK3? gene expression interact to regulate emotional brain responsiveness and stability in humans. These observations uncovered a GSK3?/FXR1P signaling pathway that contributes to regulating mood and emotion processing. Regulation of FXR1P by GSK3? also provides a mechanistic framework that may explain how inhibition of GSK3? 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.

SUBMITTER: Del'Guidice T

PROVIDER: S-EPMC4547302 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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FXR1P is a GSK3β substrate regulating mood and emotion processing.

Del'Guidice Thomas T Latapy Camille C Rampino Antonio A Khlghatyan Jivan J Lemasson Morgane M Gelao Barbara B Quarto Tiziana T Rizzo Giuseppe G Barbeau Annie A Lamarre Claude C Bertolino Alessandro A Blasi Giuseppe G Beaulieu Jean-Martin JM

Proceedings of the National Academy of Sciences of the United States of America 20150803 33

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 facilitat ...[more]

PMID: 26240334

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Project description:ObjectiveDepression and bipolar disorder (negative mood disorders, NMD) are associated with dysregulated hypothalamic-pituitary-adrenal (HPA)-axis function and disrupted emotion processing. The neural networks involved in attenuation of HPA-axis reactivity overlap with the circuitry involved in perception and modulation of emotion; however, direct links between these systems are understudied. This study investigated whether cortisol activity prior to undergoing fMRI was related to neural processing of emotional information in participants with NMD.MethodsForty-one adults (Mage=40.33, SD=15.57) with major depression (n=29) or bipolar disorder (n=12) and 23 healthy control comparisons (Mage=36.43, SD=17.33) provided salivary cortisol samples prior to completing a facial emotion perception test during 3-Tesla fMRI.ResultsOverall, pre-scan cortisol level was positively associated with greater engagement of the dorsal anterior cingulate (dACC), inferior parietal lobule, insula, putamen, precuneus, middle and medial frontal and postcentral gyri, posterior cingulate, and inferior temporal gyrus during emotion processing of all faces. NMD status moderated this effect; in NMD participants' pre-scan cortisol was associated with attenuated activation of the insula, postcentral gyrus, precuneus, and putamen for fearful faces and the medial frontal gyrus for angry faces relative to HCs. Cortisol-related attenuation of activation among NMD participants was also observed for facial identification in the dACC, putamen, middle temporal gyrus, precuneus, and caudate.ConclusionsAcross all participants, cortisol was associated with greater activation in several regions involved in the perception and control of emotion. However, cortisol responsivity was associated with hypoactivation of several of these regions in the NMD group, suggesting that HPA-axis activity may selectively interfere with the potentially adaptive recruitment of circuits supporting emotion perception, processing and/or regulation in mood disorders.

Project description:ImportanceThe development of adverse clinical outcomes in patients with psychosis has been associated with behavioral and neuroanatomical deficits related to emotion processing. However, the association between alterations in brain regions subserving emotion processing and clinical outcomes remains unclear.ObjectiveTo examine the association between alterations in emotion processing and regional gray matter volumes in individuals at clinical high risk (CHR) for psychosis, and the association with subsequent clinical outcomes.Design, setting, and participantsThis naturalistic case-control study with clinical follow-up at 12 months was conducted from July 1, 2010, to August 31, 2016, and collected data from 9 psychosis early detection centers (Amsterdam, Basel, Cologne, Copenhagen, London, Melbourne, Paris, The Hague, and Vienna). Participants (213 individuals at CHR and 52 healthy controls) were enrolled in the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) project. Data were analyzed from October 1, 2018, to April 24, 2019.Main measures and outcomesEmotion recognition was assessed with the Degraded Facial Affect Recognition Task. Three-Tesla magnetic resonance imaging scans were acquired from all participants, and gray matter volume was measured in regions of interest (medial prefrontal cortex, amygdala, hippocampus, and insula). Clinical outcomes at 12 months were evaluated for transition to psychosis using the Comprehensive Assessment of At-Risk Mental States criteria, and the level of overall functioning was measured through the Global Assessment of Functioning [GAF] scale.ResultsA total of 213 individuals at CHR (105 women [49.3%]; mean [SD] age, 22.9 [4.7] years) and 52 healthy controls (25 women [48.1%]; mean [SD] age, 23.3 [4.0] years) were included in the study at baseline. At the follow-up within 2 years of baseline, 44 individuals at CHR (20.7%) had developed psychosis and 169 (79.3%) had not. Of the individuals at CHR reinterviewed with the GAF, 39 (30.0%) showed good overall functioning (GAF score, ?65), whereas 91 (70.0%) had poor overall functioning (GAF score, <65). Within the CHR sample, better anger recognition at baseline was associated with worse functional outcome (odds ratio [OR],?0.88; 95% CI,?0.78-0.99; P?=?.03). In individuals at CHR with a good functional outcome, positive associations were found between anger recognition and hippocampal volume (ze?=?3.91; familywise error [FWE] P?=?.02) and between fear recognition and medial prefrontal cortex volume (z?=?3.60; FWE P?=?.02), compared with participants with a poor outcome. The onset of psychosis was not associated with baseline emotion recognition performance (neutral OR, 0.93; 95% CI, 0.79-1.09; P?=?.37; happy OR, 1.03; 95% CI, 0.84-1.25; P?=?.81; fear OR, 0.98; 95% CI, 0.85-1.13; P?=?.77; anger OR, 1.00; 95% CI, 0.89-1.12; P?=?.96). No difference was observed in the association between performance and regional gray matter volumes in individuals at CHR who developed or did not develop psychosis (FWE P?<?.05).Conclusions and relevanceIn this study, poor functional outcome in individuals at CHR was found to be associated with baseline abnormalities in recognizing negative emotion. This finding has potential implications for the stratification of individuals at CHR and suggests that interventions that target socioemotional processing may improve functional outcomes.

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FXR1P is a GSK3? substrate regulating mood and emotion processing.

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FXR1P is a GSK3β substrate regulating mood and emotion processing.

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