Earlier studies have shown widespread alterations of functional connectivity of various brain networks in schizophrenia, including the default mode network (DMN). The DMN has also an important role in the performance of cognitive tasks. Furthermore, treatment with second-generation antipsychotic drugs may ameliorate to some degree working memory (WM) deficits and related brain activity. The aim of this study was to evaluate the effects of treatment with olanzapine monotherapy on functional connectivity among brain regions of the DMN during WM. Seventeen patients underwent an 8-week prospective study and completed two functional magnetic resonance imaging (fMRI) scans at 4 and 8 weeks of treatment during the performance of the N-back WM task. To control for potential repetition effects, 19 healthy controls also underwent two fMRI scans at a similar time interval. We used spatial group-independent component analysis (ICA) to analyze fMRI data. Relative to controls, patients with schizophrenia had reduced connectivity strength within the DMN in posterior cingulate, whereas it was greater in precuneus and inferior parietal lobule. Treatment with olanzapine was associated with increases in DMN connectivity with ventromedial prefrontal cortex, but not in posterior regions of DMN. These results suggest that treatment with olanzapine is associated with the modulation of DMN connectivity in schizophrenia. In addition, our findings suggest critical functional differences in the regions of DMN.

Personality traits related to emotion processing are, at least in part, heritable and genetically determined. Dopamine D 2 receptor signaling is involved in modulation of emotional behavior and activity of associated brain regions such as the amygdala and the prefrontal cortex. An intronic single nucleotide polymorphism within the D 2 receptor gene (DRD2) (rs1076560, guanine Ͼ thymine or G Ͼ T) shifts splicing of the two protein isoforms (D 2 short, mainly presynaptic, and D 2 long) and has been associated with modulation of memory performance and brain activity. Here, our aim was to investigate the association of DRD2 rs1076560 genotype with personality traits of emotional stability and with brain physiology during processing of emotionally relevant stimuli. DRD2 genotype and Big Five Questionnaire scores were evaluated in 134 healthy subjects demonstrating that GG subjects have reduced "emotion control" compared with GT subjects. Functional magnetic resonance imaging in a sample of 24 individuals indicated greater amygdala activity during implicit processing and greater dorsolateral prefrontal cortex (DLPFC) response during explicit processing of facial emotional stimuli in GG subjects compared with GT. Other results also demonstrate an interaction between DRD2 genotype and facial emotional expression on functional connectivity of both amygdala and dorsolateral prefrontal regions with overlapping medial prefrontal areas. Moreover, rs1076560 genotype is associated with differential relationships between amygdala/DLPFC functional connectivity and emotion control scores. These results suggest that genetically determined D 2 signaling may explain part of personality traits related to emotion processing and individual variability in specific brain responses to emotionally relevant inputs.

A common nonsynonymous single nucleotide polymorphism leading to a serine-to-cysteine substitution at amino acid 704 (Ser 704 Cys) in the DISC1 protein sequence has been recently associated with schizophrenia and with specific hippocampal abnormalities. Here, we used multimodal neuroimaging to investigate in a large sample of healthy subjects the putative association of the Ser 704 Cys DISC1 polymorphism with in vivo brain phenotypes including hippocampal formation (HF) gray matter volume and function (as assessed with functional MRI) as well as HF functional coupling with the neural network engaged during encoding of recognition memory. Individuals homozygous for DISC1 Ser allele relative to carriers of the Cys allele showed greater gray matter volume in the HF. Further, Ser ⁄ Ser subjects exhibited greater engagement of the HF together with greater HF-dorsolateral prefrontal cortex functional coupling during memory encoding, in spite of similar behavioral performance. These findings consistently support the notion that Ser 704 Cys DISC1 polymorphism is physiologically relevant. Moreover, they support the hypothesis that genetic variation in DISC1 may affect the risk for schizophrenia by modifying hippocampal gray matter and function.

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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.