Evidence of an interaction between FXR1 and GSK3β polymorphisms on levels of Negative Symptoms of Schizophrenia and their response to antipsychotics

Abstract

Introduction: Genome Wide Association Studies (GWAS) have identified several genes associated with schizophrenia (SCZ) and exponentially increased knowledge on the genetic basis of the disease. Additionally, products of GWAS genes interact with neuronal factors coded by genes lacking association, such that this interaction may confer risk for specific phenotypes of this brain disorder. In this regard, FXR1 (Fragile-X mental-retardation-syndrome-related 1) gene has been GWAS associated with SCZ. FXR1 protein is regulated by Glycogen Synthase Kinase-3 (GSK3 ), which has been implicated in pathophysiology of SCZ and response to Antipsychotics (APs). rs496250 and rs12630592, two eQTLs of FXR1 and GSK3 respectively, interact on emotion stability and amygdala/PFC activity during emotion processing. These two phenotypes are associated with Negative Symptoms (NS) of SCZ suggesting that the interaction between these SNPs may also affect NS severity and responsiveness to medication. Methods:To test this hypothesis, in two independent samples of patients with SCZ, we investigated rs496250 by rs12630592 interaction on NS severity and response to APs. We also tested a putative link between APs administration and fxr1 expression, as already reported for GSK3 expression. Results:We found that rs496250 and rs12630592 interact on NS severity. We also found evidence suggesting interaction of these polymorphisms also on response to APs. This interaction was not present when looking at positive and general psychopathology scores. Furthermore, chronic olanzapine administration led to a reduction of FXR1 expression in mouse frontal cortex. Discussion: Our findings suggest that, like GSK3 , FXR1 is affected by APs while shedding new light on the role of the FXR1/GSK3 pathway for NS of SCZ.

Inhibition of glycogen synthase kinase 3 by lithium, a mechanism in search of specificity

“…Targeting GSK3β or overexpressing FXR1 in the mouse prefrontal cortex led to behavioral effects similar to those of lithium and other mood stabilizers on anxiety-like behavioral dimensions in mice ( Latapy et al, 2012 ; Del'Guidice et al, 2015 ; Khlghatyan and Beaulieu, 2020 ). Furthermore, human SNPs affecting the expression of GSK3B and FXR1 genes in the human prefrontal cortex were shown to interact and affect emotional stability in controls, negative symptoms and antipsychotic drug responsiveness in schizophrenia, as well as symptom severity in bipolar disorder ( Del'Guidice et al, 2015 ; Bureau et al, 2017 ; Rampino et al, 2021 ).…”

Molecular mechanisms of antipsychotics – their influence on intracellular signaling pathways, and epigenetic and post-transcription processes

“…SNPs (signal nucleotides polymorphisms) of GSK-3β are described to be risk factors for schizophrenia. The synthesis of glycogen is regulated by two subunits of GSK-3 (α and β) [ 9 ]. AKT plays a role in cognition through its modulation of long-term potentiation, synaptic plasticity and, in consequence, working memory [ 10 ].…”

“…Antipsychotics acting as DRD2 antagonists inhibit the assembly and activation of the complex of β-arrestin, PP2A and AKT. Next, the prevention of β-arrestin 2/PP2A recruitment leads to phosphorylation and the activation of AKT and, in consequence, the AKT signaling is not inhibited [ 9 , 13 ]. AKT is a convergent antipsychotic signaling mechanism.…”

“…SNPs (signal nucleotides polymorphisms) of GSK-3b are described to be risk factors for schizophrenia. The synthesis of glycogen is regulated by two subunits of GSK-3 (α and β) [9]. AKT plays intracellular pathways, and epigenetic (DNA methylation and histone modification) and post-transcription (microRNA) processes.…”

Effects of Glycogen Synthase Kinase-3 Beta Gene Polymorphisms on the Plasma Concentration of Aripiprazole in Chinese Patients with Schizophrenia

“…Previous studies have suggested that SNPs of the GSK3β gene can increase GSK3β promoter activity and alter transcriptional strength and splicing (Li M et al 2011; Kwok et al 2005). Other studies have indicated that GSK3β polymorphisms affect prefrontal cortical thickness, temporal lobe volume, and negative symptoms in schizophrenia (Blasi et al 2013;Benedetti et al 2010;Rampino et al 2021). This indicates that GSK3β polymorphism may be related to susceptibility to schizophrenia.…”