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BackgroundThe GluN2B subunit of N-methyl-d-aspartate receptors is crucially involved in the physiology of the prefrontal cortex during working memory (WM). Consistently, genetic variants in the GluN2B coding gene (GRIN2B) have been associated with cognitive phenotypes. However, it is unclear how GRIN2B genetic variation affects gene expression and prefrontal cognitive processing. Using a composite score, we tested the combined effect of GRIN2B variants on prefrontal activity during WM performance in healthy subjects.MethodWe computed a composite score to combine the effects of single nucleotide polymorphisms on post-mortem prefrontal GRIN2B mRNA expression. We then computed the composite score in independent samples of healthy participants in a peripheral blood expression study (n = 46), in a WM behavioural study (n = 116) and in a WM functional magnetic resonance imaging study (n = 122).ResultsFive polymorphisms were associated with GRIN2B expression: rs2160517, rs219931, rs11055792, rs17833967 and rs12814951 (all corrected p < 0.05). The score computed to account for their combined effect reliably indexed gene expression. GRIN2B composite score correlated negatively with intelligence quotient, WM behavioural efficiency and dorsolateral prefrontal cortex activity. Moreover, there was a non-linear association between GRIN2B genetic score and prefrontal activity, i.e. both high and low putative genetic score levels were associated with high blood oxygen level-dependent signals in the prefrontal cortex.ConclusionsMultiple genetic variants in GRIN2B are jointly associated with gene expression, prefrontal function and behaviour during WM. These results support the role of GRIN2B genetic variants in WM prefrontal activity in human adults. [ABSTRACT FROM PUBLISHER]

BackgroundEmotion dysregulation is a key feature of schizophrenia, a brain disorder strongly associated with genetic risk and aberrant dopamine signalling. Dopamine is inactivated by catechol-O-methyltransferase (COMT), whose gene contains a functional polymorphism (COMT Val158Met) associated with differential activity of the enzyme and with brain physiology of emotion processing. The aim of the present study was to investigate whether genetic risk for schizophrenia and COMT Val158Met genotype interact on brain activity during implicit and explicit emotion processing.MethodA total of 25 patients with schizophrenia, 23 healthy siblings of patients and 24 comparison subjects genotyped for COMT Val158Met underwent functional magnetic resonance imaging during implicit and explicit processing of facial stimuli with negative emotional valence.ResultsWe found a main effect of diagnosis in the right amygdala, with decreased activity in patients and siblings compared with control subjects. Furthermore, a genotype × diagnosis interaction was found in the left middle frontal gyrus, such that the effect of genetic risk for schizophrenia was evident in the context of the Val/Val genotype only, i.e. the phenotype of reduced activity was present especially in Val/Val patients and siblings. Finally, a complete inversion of the COMT effect between patients and healthy subjects was found in the left striatum during explicit processing.ConclusionsOverall, these results suggest complex interactions between genetically determined dopamine signalling and risk for schizophrenia on brain activity in the prefrontal cortex during emotion processing. On the other hand, the effects in the striatum may represent state-related epiphenomena of the disorder itself. [ABSTRACT FROM PUBLISHER]

Sounds, like music and noise, are capable of reliably affecting individuals’ mood and emotions. However, these effects are highly variable across individuals. A putative source of variability is genetic background. Here we explored the interaction between a functional polymorphism of the dopamine D2 receptor gene ( DRD2 rs1076560, G > T, previously associated with the relative expression of D2S/L isoforms) and sound environment on mood and emotion-related brain activity. Thirty-eight healthy subjects were genotyped for DRD2 rs1076560 (G/G = 26; G/T = 12) and underwent functional magnetic resonance imaging (fMRI) during performance of an implicit emotion-processing task while listening to music or noise. Individual variation in mood induction was assessed before and after the task. Results showed mood improvement after music exposure in DRD2 GG subjects and mood deterioration after noise exposure in GT subjects. Moreover, the music, as opposed to noise environment, decreased the striatal activity of GT subjects as well as the prefrontal activity of GG subjects while processing emotional faces. These findings suggest that genetic variability of dopamine receptors affects sound environment modulations of mood and emotion processing. [ABSTRACT FROM AUTHOR]

Background Rasd2 is a striatal GTP-binding protein that modulates Akt and mTOR signaling cascades, well known to be highly vulnerable pathways in psychiatric disorders. Aims We investigated the association of Rasd2 and its genetic variation with a series of prefronto-striatal phenotypes related to psychosis in rodents and humans. Objectives We want to provide evidence that Rasd2 controls the vulnerability to schizophrenia-related behavior induced by psychothomimetic drugs in mice. Moreover, we aim to find genetic variations within the Rasd2 gene that influence a series of brain schizophrenia-related phenotypes in human. Methods Rasd2 knockout mice were employed to evaluate schizophrenia-like behaviors induced by psychotomimetic drugs like amphetamine and phencyclidine. Furthermore, we investigated if RASD2 genetic variations in humans are associated with mRNA expression in post-mortem prefrontal cortex, as well as prefrontal and striatal grey matter volume and physiology during working memory as measured with MRI in healthy subjects. Finally, we assessed RASD2 mRNA expression levels in post-mortem brains of patients with schizophrenia and bipolar disorder. Results We found that both psychotomimetics triggered greater vulnerability to motor stimulation and to prepulse inhibition deficits in Rasd2 mutants. In humans, we found that a genetic variation (rs6518956) within RASD2 predicts prefrontal mRNA expression as well as prefrontal grey matter volume and prefronto-striatal activity during working memory. Finally, we reported that RASD2 mRNA expression is slightly reduced in post-mortem prefrontal cortex of patients with schizophrenia. Conclusions Collectively, our data suggests that RASD2 represents a gene of potential interest in psychiatric disorders for its ability to modulate prefronto-striatal phenotypes related to schizophrenia. [ABSTRACT FROM AUTHOR]