Association of GSK-3β Genetic Variation With GSK-3β Expression, Prefrontal Cortical Thickness, Prefrontal Physiology, and Schizophrenia

Abstract

OBJECTIVE Glycogen synthase kinase 3β (GSK-3β) is an enzyme implicated in neurodevelopmental processes with a broad range of substrates mediating several canonical signaling pathways in the brain. The authors investigated the association of variation in the GSK-3β gene with a series of progressively more complex phenotypes of relevance to schizophrenia, a neurodevelopmental disorder with strong genetic risk. METHOD Based on computer predictions, the authors investigated in humans the association of GSK-3β functional variation with 1) GSK-3β mRNA expression from postmortem prefrontal cortex, 2) GSK-3β and β-catenin protein expression from peripheral blood mononuclear cells (PBMCs), 3) prefrontal imaging phenotypes, and 4) diagnosis of schizophrenia. RESULTS Consistent with predictions, the TT genotype of a single-nucleotide polymorphism in GSK-3β (rs12630592) was associated with reduced GSK-3β mRNA from postmortem prefrontal cortex. Furthermore, this genotype was associated with GSK-3β protein expression and kinase activity, as well as with downstream effects on β-catenin expression in PBMCs. Finally, the TT genotype was associated with attenuated functional MRI prefrontal activity, reduced prefrontal cortical thickness, and diagnosis of schizophrenia. CONCLUSIONS These results suggest that GSK-3β variation is implicated in multiple phenotypes relevant to schizophrenia.

Variation in Dopamine D2 and Serotonin 5-HT2A Receptor Genes is Associated with Working Memory Processing and Response to Treatment with Antipsychotics

“…Furthermore, we also found that individuals carrying the T allele in both genes also have lower behavioral accuracy during working memory in a large sample of healthy subjects. Previous studies have indicated that genetic variability in healthy subjects drives variation in prefrontal activity (Blasi et al, 2013b;Huffaker et al, 2009) and lowers behavioral performance (Goldberg et al, 2003). All together, these findings are reminiscent of results in patients with schizophrenia (Callicott et al, 2000), and they have been interpreted as the need for greater recruitment of cortical resources to perform the task with reduced or similar behavioral proficiency (Bertolino and Blasi, 2009a;Manoach, 2003).…”

“…Thus, genetically induced levels of 5-HT2A receptors may in turn interact with lower or greater expression of D2L postsynaptic receptors as a function of DRD2 variation in determining differential levels of stimulation of prefrontal pyramidal neurons or interneurons of relevance for cognitive processing. Another synergistic or alternative mechanism of the combined effect of rs1076560 and rs6314 on working memory processing is that stimulation of D2 and 5-HT2A receptors implicates intraneuronal adjustments that modulate common pathways including molecules such as AKT1 and GSK3beta (Beaulieu, 2012;de Bartolomeis et al, 2013), whose expression and related genetic variation have been associated with schizophrenia (Blasi et al, 2011(Blasi et al, , 2013bTan et al, 2008). In line with the relevance of common signaling cascades, current evidence also suggests that the cross-talk between D2 and 5-HT2A may be facilitated by the assembly of heteromers (Albizu et al, 2011;de Bartolomeis et al, 2013;Fuxe et al, 2014).…”

Functional Genetic Variation of the Cannabinoid Receptor 1 and Cannabis Use Interact on Prefrontal Connectivity and Related Working Memory Behavior

“…Fetal brains of this collection were excluded from the analysis because of their limited sample size (http:// braincloud.jhmi.edu/). Details of informed consent, ethics, autopsy, tissue acquisition, handling processing, dissection, clinical characterization, diagnoses, neuropathological examinations, toxicological analysis, RNA extraction, quality control measures, and DNA evaluation from cerebellar tissue were described previously (Colantuoni et al, 2011;Blasi et al, 2013a;Blasi et al, 2013b).…”

“…All preprocessing was performed as described previously (Blasi et al, 2013b). Following preprocessing, all fMRI data were analyzed using General Linear Model (GLM) to detect changes in brain activity based on a priori task design and hemodynamic response function.…”

“…We used a family-wise small volume-corrected statistical threshold of p value o0.05 (minimum cluster size [k] ¼ 5), using as volume of interest the Wake Forest University PickAtlas (http://fmri.wfubmc.edu/cms/software #PickAtlas) Brodmann's areas (BAs) of the dorsolateral PFC (DLPFC). These regions of interest were a priori chosen based on our investigation of prefrontal phenotypes and on the well-established association between the n-back task and activity in the dorsolateral PFC (Bertolino et al, 2010;Blasi et al, 2013b).…”