Schizophrenia is a complex psychiatric disease with a strong genetic predisposition. Linkage and association studies in different ethnic populations implicate Neuregulin 1 (NRG1) as a candidate susceptibility gene for schizophrenia. NRG1 functions by interacting with ErbB tyrosine kinase receptors and plays a critical role in neuronal migration and differentiation and central nervous system development. NRG1-ErbB signaling could lead to a variety of abnormal neurodevelopmental events that have been implicated in the underlying pathology of schizophrenia (SCZ). Here we show in a cell-model system, that B lymphoblasts migrate to NRG1 through the ErbB-signaling system as observed in neuronal cells. We assessed NRG1-induced cell migration in B lymphoblasts from patients SCZ and found that NRG1-induced migration is significantly decreased compared with control individuals in 2 independent cohorts. The magnitude of NRG1-induced migration is associated with polymorphisms of the NRG1 and catechol-o-methyltransferase (COMT) genes and with an epistatic interaction of these genes. Our findings confirmed that the functional COMT val to met mutation does, in fact influence NRG1-mediated cell migration. The COMT enzyme, which is responsible for dopamine catabolism has been shown to influence cortical dopaminergic signaling and function, presumably since dopamine transporters are relatively scarce in this region. Consistent with the hypothesis that val is a risk allele, the subjects carrying the val/val genotype evinced significantly lower NRG1-mediated migration compared with those carrying Met/Met alleles. Moreover, severe defects in NRG1-stimulated phosphorylation of AKT1 were observed at least in some Val/Val subjects. These results suggest a novel biological effect of COMT potentially related to schizophrenia pathogenesis, and indicate an epistatic interaction of these genes at a biological level. It is generally assumed that multiple genes interact with each other and with the environment to account for the risk architecture of SCZ, but to our knowledge, this is the first demonstration of biologic epistasis between putative schizophrenia risk genes. This study demonstrates the migratory response of schizophrenia-derived cells to NRG1 is impaired and is associated with genetic variations in more than one schizophrenia susceptibility gene, providing a novel insight into potential neurodevelopmental mechanisms of SCZ. If common genes shared by neuronal cells and lymphocytes regulate NRG1-induced migration, this suggest that NRG1-mediated neural migration may be abnormal in patients with SCZ during development. Although controversial, aberrant neuronal migration has been suspected from reports of cytoarchitectural abnormalities in the cortex of patients with SCZ. Thus, our findings suggest a potential molecular pathway involved in the neurodevelopmental origins of schizophrenia. In a current study, we examine cell adhesion, as an essential component of cell motility. In our assay, NRG1 induces lymphoblasts to assume varying levels of adhesion characterized by time-dependent fluctuations in the firmness of attachment. NRG1 alpha-induced adhesion variation is blocked by ErbB2, PI3K, and AKT inhibitors, but not by PLC, ROCK, MLCK or MEK inhibitors, implicating the ErbB2/PI3K/AKT1 signaling pathway in NRG1-stimulated, integrin-mediated cell adhesion. In cell lines from 20 SCZ and 20 healthy controls, cells from SCZ showed significant deficiency in the range of NRG1 alpha-induced adhesion. The COMT val158met genotype demonstrates a strong trend towards predicting the range of the NRG1 alpha-induced adhesion response with risk homozygotes having decreased variation in cell adhesion even in healthy controls. Our findings suggest that a mechanism of the NRG1 genetic association with SCZ may involve the molecular biology of cell adhesion.? ? AKT1-dependent molecular pathways control diverse aspects of cellular development and adaptation, including interactions with neuronal dopaminergic signaling. If AKT1 has an impact on dopaminergic signaling, then genetic variation in AKT1 would be associated with brain phenotypes related to cortical dopaminergic function. In this study we provide evidence that a coding variation in AKT1 that affects protein expression in human B lymphoblasts, influences several brain measures related to dopamine function. Cognitive performance linked to frontostriatal circuitry, prefrontal physiology during executive function, and frontostriatal gray-matter volume on MRI were altered in subjects with AKT1 variation. Neuroimaging measures show a main affect of the AKT1 genotype, with significant epistasis with the functional COMT val158met mutation, a gene that indexes cortical synaptic dopamine. This genetic interaction is consistent with the putative role of AKT1 in dopamine signaling. We also found that this AKT1 variant was associated with risk for schizophrenia (SCZ). These data implicate AKT1 in modulating human prefrontal-striatal structure and function and suggests that the mechanism of this effect may be coupled to dopamine signaling and relevant to the expression of psychosis.? ? The schizophrenia gene dystrobrevin-binding protein (DTNBP1) encodes dysbindin, with its binding partner MUTED is an essential component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Dysbindin expression is reduced in SCZ brain tissue, but the molecular mechanisms by which this contributes to pathogenesis and symptomology are unknown. Here we studied the effects of DTNBP1 siRNA on cell surface levels of dopamine D2 receptor (DRD2). DTNBP1 siRNA decreased dysbindin protein, increased cell surface DRD2 and blocked dopamine-induced DRD2 internalization. In contrast, decreased dysbindin did not change dopamine D1 receptor (DRD1) levels, or its basal or dopamine-induced internalization. This is the first demonstration of a SCZ susceptibility gene exerting a functional effect on DRD2 signaling, a pathway that has long been implicated in the illness. We propose a molecular mechanism for pathogenesis on which risk alleles in DTNBP1 compromise the ability of BLOC-1 to traffic DRD2 toward degradation, but has little effect on DRD1 trafficking. Impaired trafficking of DRD2 decreases dopamine-induced internalization, and with more receptors retained on the cell surface, dopamine stimulation produces excess intracellular signaling. Such an increase in DRD2 signaling relative to DRD1 would contribute to the imbalances in dopamine neurotransmission characteristic of schizophrenia.
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