Genes are major contributors to many psychiatric diseases, but their mechanisms of action have long seemed elusive. To date, we have evidence of association with schizophrenia in our family datasets of at least the following genes: COMT, DTNBP1, MUTED, EAA1, MRDS1, GAD1, DISC1, FEZ1, CITRON, NDE1, NRG1, PIK3d, ErbB4, DLG4, LIS1, MHTFR, DRD2, CAPON, PPP1R1B, DAARP, GRM3, CHRNA7, KCNH2, SREB2, PRODH, CAMKIIa, AKT1, FGF20, RELN1, and RCCX. Our dataset consists of individuals from over 750 families and case/control datasets of over 650. The unique aspects of our dataset, which may explain the strength of the genetic associations that have emerged, is that every subject, both cases and controls, are evaluated extensively with structured on sight interviews by the same clinicians who have worked together on this project for over ten years. As characterization of single genetic variant rapidly proceeds, research increasingly turns to dissecting gene-gene and gene-environment interactions. Our strategy for characterizing and mapping gene effects in brain with cognitive and neuroimaging assays enables us to better define intermediate phenotypes. Here we outline recent advances of linking genes to structural and functional variation in brain systems related to cognition and emotion. One study looked at a common polymorphism, COMT val158met, which has been shown to affect dopamine tone in cortex and cortical functioning. D1 receptors are the main DA receptors in the cortex, and studies have shown that decreased levels of cortical DA are associated with upregulation of D1 receptor availability, as measured with PET radiotracer NNC112. We compared NNC112 binding in val/val normal controls versus met allele carriers. Val/val subjects had significantly higher cortical NNC112 binding compared with Met carriers, but did not differ in striatal binding. These results confirm the prominent role of COMT in regulating DA transmission in cortex but not striatum, and the reliability of NNC112 as a marker for low DA tone as previously suggested by studies in schizophrenia. For the first time we have shown in the human brain that the val158met polymorphism is a genetic factor accounting for variability across individuals in D1 receptor availability. An example of structural impact is the G protein-coupled receptor (GPCR) which is highly diversified and involved in many forms of information processing. SREB2 (superconserved receptor expressed in brain) is the most conserved GPCR throughout vertebrate evolution and is expressed abundantly in brain structures exhibiting high levels of plasticity, such as hippocampal dendate gyrus. Here, we show that SREB2 is involved in determining brain size, modulating diverse behaviors, and potentially in vulnerability to SCZ. Mild overexpression of SEB2 caused significant brain weight reduction and ventricular enlargement in transgenic mice as well as behavioral abnormalities mirroring psychiatric disorders. SREB2 knockout mice showed a reciprocal phenotype, a significant increase in brain weight accompanying a trend toward enhanced memory without apparent other behavior abnormalities. Because of phenotypic overlap between SREB2 transgenic mice and schizophrenia, we sought a possible link between the two. Minor alleles of two SREB2 variants were over-transmitted to the schizophrenia family-based sample and showed an allele load association with reduced hippocampal gray matter volume in patients. Our data implicate SREB2 as a potential risk factor for psychiatric disorders and its pathway as a target for psychiatric therapy. Our present data warrant further studies investigating brain disorders. Toward this end, specific agonists and antagonist for SREB2 should be powerful tools and may eventually lead directly to development of therapeutics for neuropsychiatric disorders.? ? Our findings on the neurobiological mechanism of the NRG1 schizophrenia susceptibility gene demonstrated impairment in NRG1-mediated cell migration. Using a B lymphoblast cell model we examined cell adhesion, an essential component process of cell motility. NRG1 induces lymphoblasts to assume varying levels of adhesion characterized by time-dependent fluctuations in the firmness of attachment. In cell lines from patients and controls, patients showed significant deficiency in the range of NRG1 induced adhesion. We also found a COMT val158met genotype effect showing a strong trend towards predicting the range of the NRG1-induced adhesion response with val/val having decreased variation in cell adhesion even in controls. Our findings suggest that a mechanism of the NRG1 genetic association with schizophrenia may involve the molecular biology of cell adhesion.? ? This year we also investigated the impact of environment on risk for disease. We investigated how an early stressor, like parental separation, is a vulnerability factor in mood disorder. In common marmoset monkeys, daily deprivation during infancy produces a pro-depressive state of increased basal activity and reactivity in stress systems and mild anhedonia that persists at least to adolescence. We examined genes implicated in neural plasticity and in the pathophysiology of mood disorder, in the hippocampus of these same adolescent marmosets. We found effects on hippocampal gene expression, suggestive of changes in synaptic functioning and plasticity. The data suggest that hippocampal involvement in the disorder begins prior to the first episode of illness, and may reflect the role that early developmental adversity plays in its origins. ? ? We also looked to see if a preexisting condition, like childhood enuresis, could be a premorbid marker for neurodevelopmental abnormalities related to schizophrenia and found that there were higher rates of childhood enuresis (21%) compared with sibling (11%) or controls (7%). Patients with enuresis performed worse on cognitive tests as compared with non-enuresis patients. ? ? Recent findings, implicate complement in neurogenesis, synapse remodeling and pruning during brain developmental processes contribute to schizophrenia susceptibility. The role of complement, has been examined. Increased activity of C1, C3, C4 complement components in schizophrenia has been reported by other groups. Two studies on different subject cohorts showed increased MBL-MASP-2 activity, it is likely that the disorder is accompanied by alterations of the complement classical and lectin pathways, which undergoes dynamic changes, depending on the illness course and the state of neuroimmune crosstalk. It is plausible that the multicomponent complement system has an association with schizophrenia susceptibility, pathopsychology and illness course. For which understanding may bring a new perspective for possible immunomodulation and immunocorrection of the disease.? ? The complex organization of connectivity in the human brain is incompletely understood. Here we show using anatomical networks derived from analysis of inter-regional covariation of gray matter volume in MRI data on controls, that classical divisions of cortex (multimodal, unimodal, and transmodal) have some distinct topological attributes. We found the multimodal network had a hierarchical organization dominated by frontal hubs with low clustering, transmodal netmodal as assortative. We propose that the topological differences between divisions of normal cortex may represent the outcome of different growth processes for multimodal and transmodal networks and that neurodevelopmental abnormalities in schizophrenia specifically impact multimodal cortical organization.
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