Bart Rutten

Epigenetic regulation of the BDNF gene: implications for psychiatric disorders.

Abnormal brain-derived neurotrophic factor (BDNF) signaling seems to have a central role in the course and development of various neurological and psychiatric disorders. In addition, positive effects of psychotropic drugs are known to activate BDNF-mediated signaling. Although the BDNF gene has been associated with several diseases, molecular mechanisms other than functional genetic variations can impact on the regulation of BDNF gene expression and lead to disturbed BDNF signaling and associated pathology. Thus, epigenetic modifications, representing key mechanisms by which environmental factors induce enduring changes in gene expression, are suspected to participate in the onset of various psychiatric disorders. More specifically, various environmental factors, particularly when occurring during development, have been claimed to produce long-lasting epigenetic changes at the BDNF gene, thereby affecting availability and function of the BDNF protein. Such stabile imprints on the BDNF gene might explain, at least in part, the delayed efficacy of treatments as well as the high degree of relapses observed in psychiatric disorders. Moreover, BDNF gene has a complex structure displaying differential exon regulation and usage, suggesting a subcellular- and brain region-specific distribution. As such, developing drugs that modify epigenetic regulation at specific BDNF exons represents a promising strategy for the treatment of psychiatric disorders. Here, we present an overview of the current literature on epigenetic modifications at the BDNF locus in psychiatric disorders and related animal models.

An environmental analysis of genes associated with schizophrenia: hypoxia and vascular factors as interacting elements in the neurodevelopmental model

Investigating and understanding gene–environment interaction (G × E) in a neurodevelopmentally and biologically plausible manner is a major challenge for schizophrenia research. Hypoxia during neurodevelopment is one of several environmental factors related to the risk of schizophrenia, and links between schizophrenia candidate genes and hypoxia regulation or vascular expression have been proposed. Given the availability of a wealth of complex genetic information on schizophrenia in the literature without knowledge on the connections to environmental factors, we now systematically collected genes from candidate studies (using SzGene), genome-wide association studies (GWAS) and copy number variation (CNV) analyses, and then applied four criteria to test for a (theoretical) link to ischemia–hypoxia and/or vascular factors. In all, 55% of the schizophrenia candidate genes (n=42 genes) met the criteria for a link to ischemia–hypoxia and/or vascular factors. Genes associated with schizophrenia showed a significant, threefold enrichment among genes that were derived from microarray studies of the ischemia–hypoxia response (IHR) in the brain. Thus, the finding of a considerable match between genes associated with the risk of schizophrenia and IHR and/or vascular factors is reproducible. An additional survey of genes identified by GWAS and CNV analyses suggested novel genes that match the criteria. Findings for interactions between specific variants of genes proposed to be IHR and/or vascular factors with obstetric complications in patients with schizophrenia have been reported in the literature. Therefore, the extended gene set defined here may form a reasonable and evidence-based starting point for hypothesis-based testing of G × E interactions in clinical genetic and translational neuroscience studies.

Gene-Environment Interaction Research and Transgenic Mouse Models of Alzheimer's Disease

The etiology of the sporadic form of Alzheimers disease (AD) remains largely unknown. Recent evidence has suggested that gene-environment interactions (GxE) may play a crucial role in its development and progression. Whereas various susceptibility loci have been identified, like the apolipoprotein E4 allele, these cannot fully explain the increasing prevalence of AD observed with aging. In addition to such genetic risk factors, various environmental factors have been proposed to alter the risk of developing AD as well as to affect the rate of cognitive decline in AD patients. Nevertheless, aside from the independent effects of genetic and environmental risk factors, their synergistic participation in increasing the risk of developing AD has been sparsely investigated, even though evidence points towards such a direction. Advances in the genetic manipulation of mice, modeling various aspects of the AD pathology, have provided an excellent tool to dissect the effects of genes, environment, and their interactions. In this paper we present several environmental factors implicated in the etiology of AD that have been tested in transgenic animal models of the disease. The focus lies on the concept of GxE and its importance in a multifactorial disease like AD. Additionally, possible mediating mechanisms and future challenges are discussed.

Gene-Environment Interaction Research and Transgenic Mouse Models of Alzheimer's Disease (Erratum)

1 School for Mental Health and Neuroscience (MHeNS), Faculty of Health, Medicine and Life Sciences, European Graduate School of Neuroscience (EURON), Maastricht University Medical Centre, P.O. Box 616, 6200 MD Maastricht, The Netherlands 2 Department of Neuroscience, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA 3 Division of Psychological Medicine, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK 4 Department of Psychiatry, Psychosomatics and Psychotherapy, University of Würzburg, 97080 Würzburg, Germany

T132. ASSESSMENT OF CROSS-NATIONAL EQUIVALENCE OF THE COMMUNITY ASSESSMENT OF PSYCHIC EXPERIENCES (CAPE)

Abstract Background The Community Assessment of Psychic Experiences (CAPE) is a self-report questionnaire that has been developed to measure the dimensions of psychosis in the general population. The cross-national equivalence of a questionnaire allows the comparability of a scale across different populations in different countries, i.e., using different versions of the scale according to the considered language. In this study, our aim was to investigate the equivalence of the CAPE across different countries. Methods Data were drawn from the European Union Gene-Environment Interaction (EU-GEI) study. Participants (incident case of psychotic disorder, controls and siblings of cases) were recruited across in six countries: United Kingdom, the Netherlands, Italy, Spain, Brazil and France. To analyse the cross-national equivalence of the dichotomised version of the CAPE, we used the multigroup categorical confirmatory factory analysis (MCCFA). The cross-national equivalence can be stated after the establishment of three invariances characterised by increased constraints: the configural invariance, the metric invariance and the scalar invariance across the multiples groups. Results The configural invariance model fits well, providing evidence for identical factor structure across countries. The assumption that factor loadings are identical across countries is granted based on the negligible change in the fit indices in the metric invariance model. Moreover, the fit indices suggest that the CAPE shows scalar invariance across countries. Discussion These findings suggest that comparisons across countries of factor and observed means of the CAPE are possible. Thus, differences observed in scores between samples from different countries can be considered as different levels of psychosis.

5.1.2 Mentale weerbaarheid en veerkracht

Tot nog toe hebben de verschillende verschijningsvormen van stress, de mogelijke wijze van herstel of juist het stagneren hiervan centraal gestaan. Vaststaat dat er grote verschillen zijn in individuele reacties bij gelijke stressoren. Gebruikelijke verklaringsmodellen voor deze interindividuele variatie worden frequent vanuit kwetsbaarheid- of risicomodellen vormgegeven.

8.3 Posttraumatisch stress-syndroom

Carla is 28 jaar en heeft voortdurend last van nachtmerries. In deze dromen wordt zij achtervolgd door mannen met bivakmutsen, die haar met een pistool bedreigen. Deze nachtmerries zijn ontstaan nadat Carla twee jaar geleden slachtoffer was van een bankoverval. Zij werkte toen bij een bank en werd met een pistool op de slaap gedwongen geld te overhandigen. Dat gebeuren laat Carla niet los. Als zij op straat een bromfiets tegenkomt schrikt zij nog steeds (de overvallers vluchtten per bromfiets). Doordat Carla volledig verstijft als er ‘ongure types’ aan de balie komen, kan zij haar werk als bankemployee niet langer uitvoeren. Zij blijft nu veel binnen en zorgt ervoor dat de deuren goed op slot zitten. De laatste tijd is zij erg prikkelbaar en kan bij het minste of geringste kwaad worden. Haar vriendinnen zoekt zij steeds minder op; het contact is er niet meer, zij voelt zich ‘een vreemde’.