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ICOSR 2013—Creating Vulnerability via Epigenetics

22 May 2013

As part of our ongoing coverage of the 2013 International Congress on Schizophrenia Research (ICOSR), held 21-25 April in Colorado Springs, Colorado, we bring you session summaries from some of the Young Investigator Travel Award winners. For this report, we thank Monica Aas of the University of Oslo, Norway.

23 May 2013. One of the final symposia of the ICOSR, on Thursday afternoon, was “Epigenetics at the Interaction between Genetic and Environmental Risk Factors for Brain Function Related to Schizophrenia.” Several speakers were missing, leaving only Alessandro Bertolino of the University of Bari Aldo Moro, Bari, Italy, and Marco A. Riva of the University of Milan to present new epigenetic research related to schizophrenia risk, linking early stress (hypoxia and perinatal stress) to methylation and altered gene expression associated with behavior and cognitive changes.

Bertolino started the session with a talk on hypoxia-related methylation of the single nucleotide polymorphisms COMT Val158Met and BDNF Val66Met, demonstrating associations with cognitive function as well as opposite (or different) effects for Val/Val versus Met carriers.

Catechol-O-methyltransferase (COMT), a key enzyme for inactivation of prefrontal DA (Gogos et al., 1998), contains an SNP (rs4680, G→A, Val→Met) in which the ancestral Val allele is associated with greater enzyme activity, blunted stress responses, and greater prefrontal activity during working memory, that is, reduced efficiency (Egan et al., 2001; Chen et al., 2004; Papaleo et al., 2008; Mier et al., 2010; Walder et al., 2010). Notably, rs4680 in COMT exon 4 also abolishes a CpG site so that each Val allele has one CpG site and the Met allele has none. Bertolino showed, in a large sample of humans, that hypoxia is associated with greater methylation in Val/Val subjects, and with lower methylation in Val/Met subjects, compared with the same genotypes without hypoxia. Methylation is further related to reduced transcription of the gene, as well as associated with improved working memory performance based on the N-back working memory paradigm. Bertolino also showed in a study of 115 families that methylation is 20 percent heritable, and that patients with schizophrenia have greater methylation of the gene than their siblings or healthy controls.

Bertolino also presented data on BDNF Val66Met and methylation, both in healthy humans and transgenic rodents carrying the human re6265 SNP, again showing stronger methylation in the Val/Val carrier group than in the Met group. Bertolino demonstrated an interaction effect among genotype, methylation, and working memory, with significant opposite associations in BDNF Val66Met Val/Val carriers, compared to Met carriers. Bertolino concluded his talk by emphasizing the importance of expanding studies from single genes to the whole genome.

The second speaker, Marco Riva, talked about the importance of investigating both perinatal stress and later stressful events, and how these events may be related to altered methylation and, hence, altered gene expression in the prefrontal cortex. Riva presented data on the expression of brain-derived neurotrophic factor (BDNF), showing that perinatal stress is related to reduction of BDNF in the brain of adult rats. He also showed that perinatal stress in male rats is related to reduced performance on the object recognition test in the adult rat. Riva linked the above to epigenetic changes, explaining that perinatal stress increases methylation, which again is related to a reduced transcript of BDNF. He also showed that perinatal stress is associated with reduced upregulation of BDNF on the forced swim test in adult rats, linking this to impaired ability to cope under stressful situations in rats exposed to perinatal stress.

This effect appears to be reversible, as antipsychotic medication given in adolescence to perinatal stressed rats prevented BDNF reduction in the same rodent in adulthood. Riva stated that environmental enrichment might also have the same effect. Epigenetic changes in response to stress were also seen across genes: methylome analysis in the prefrontal cortex of rats exposed to perinatal stress showed that a large number of genes (3,386 genes) were methylated differently from controls. These included genes linked to bipolar disorders and schizophrenia, such as CACNA1C and DISC1, as well as the COMT gene.

Riva concluded that perinatal stress has long-lasting changes on brain function by affecting the expression of genes. He further emphasized the importance to take into account the timing of the stress exposure when investigating pathophysiological consequences of early stress.

To sum up, this symposium demonstrated the importance of taking into account the interaction between environmental factors and gene expression, as well as showing links to changes in a wide range of gene expressions. Early stress may have long-lasting changes in brain function by affecting expression of relevant genes. This is the start of a new line of exciting and hopefully fruitful research aimed at further understanding the complex etiology behind severe mental disorders—Monica Aas.