The effect of G72 genotype on neural correlates of memory encoding and retrieval
Introduction
Schizophrenia and affective disorders are caused by a combination of genetic predispositions and environmental triggers. The genetic vulnerability of an individual evolves from addition or potentiation of a specific cluster of risk variants (Lang et al., 2007, Harrison and Weinberger, 2005). Recently, several susceptibility genes for schizophrenia and affective disorders have been identified (for reviews, see Harrison and Weinberger, 2005, Owen et al., 2005, Smoller and Gardner-Schuster, 2007, Chubb et al., 2008). Among these, G72 (also named d-amino acid oxidase activator, DAOA) is one of the most frequently replicated vulnerability genes (Detera-Wadleigh and McMahon, 2006). It shows a genetic overlap across the major psychoses, such as schizophrenia (Chumakov et al., 2002, Li and He, 2007, Addington et al., 2004, Schumacher et al., 2004), bipolar disorder (Addington et al., 2004, Prata et al., 2008, Schumacher et al., 2004) and major depression (Rietschel et al., 2008), questioning the long-held view of a strict nosological separation of psychiatric disorders (Craddock et al., 2006, Craddock and Owen, 2005).
The functional mechanisms of G72 are still not fully understood. Chumakov and colleagues showed that the G72 protein (which is only known in higher primates) activates a second protein, d-amino acid oxidase (DAAO), that is involved in the mechanisms of d-serine (Chumakov et al., 2002). d-serine is an agonist at the glycine modulation site of the N-methyl-d-aspartate (NMDA) receptor (Ohi et al., 2009). Thus, G72 might work as an indirect modulator of NMDA neurotransmission, which has been implicated in various cognitive domains. The association between alterations in d-serine metabolism and schizophrenia is for example supported by studies demonstrating decreased d-serine levels in the cerebrospinal fluid and serum of schizophrenia patients (Hashimoto et al., 2003, Hashimoto et al., 2005). Furthermore, the administration of d-serine (as add-on medication) has been shown to reduce some of the symptoms in schizophrenia (Boks et al., 2007). This provides a potential link between G72 and the glutamate hypofunction hypothesis of schizophrenia (Coyle, 2006). Another study however failed to confirm the interaction between G72 and DAAO (Kvajo et al., 2008). Rather, LG72, a splicing isoform of the G72 gene, encodes for a mitochondrial protein. It was shown that an overexpression of G72 led to mitochondrial fragmentation. The authors proposed that an unknown function of the G72 in modulating mitochondrial morphology might be responsible for the risk-conferring property of the gene.
The genetic overlap between schizophrenia and affective disorders points to a low specificity of our current classification systems. Functional neuroimaging can bridge the gap between the neurobiology of genes and behavioural performance, since brain activation patterns should be closer to the actual neurobiology of gene function than cognitive measures alone (Lawrie et al., 2008, Lanzenberger and Kasper, 2005). Three recent neuroimaging investigations have examined the impact of G72 genotype on brain function. First, Goldberg et al. (2006) showed that healthy subjects carrying the homozygous high-risk T/T allele at single nucleotide polymorphisms (SNP) M24 had decreased brain activity in the right hippocampus and left parahippocampus during an episodic memory encoding task. Second, Hall et al. (2008) report for subjects with a high familial risk for schizophrenia brain activation differences between G72 genotype groups (assessed by markers M23 and M24) in the left hippocampus and parahippocampus during a verbal sentence completion task. Finally, Jansen et al. (2009) found in healthy subjects brain activation differences in the right parahippocampus between the G72 genotype groups (assessed by markers M23 and M24) during a working memory n-back task. Despite the overall heterogeneity of these functional imaging studies with regard to subjects and paradigms, they share one common result. Genetic variation in G72 influences brain activity in the medial temporal lobe (MTL), especially the hippocampus and the parahippocampus. G72 might therefore play a modulatory role on brain activity in MTL structures, an effect that might be mediated by influences on the NMDA receptor (Hall et al., 2008).
A modulation of brain activity in the MTL by G72 genotype is also plausible due to the prominent role of this brain structure in schizophrenia and affective disorders. MTL structures, especially the hippocampus and parahippocampus, are involved in the pathogenesis of affective disorders and particularly schizophrenia as has been demonstrated in numerous post mortem, structural and functional imaging studies (Harrison, 2004, Heckers, 2001). Decreases in hippocampal and parahippocampal volume in patients with schizophrenia and, to a lesser degree, in their genetic relatives have been consistently reported (Boos et al., 2007, Honea et al., 2005, Whalley et al., 2007, Wright et al., 2000). Functional imaging studies, in particular those testing episodic or relational memory, have demonstrated decreased hippocampal and, less often, parahippocampal activation in patients with schizophrenia as well as in their relatives (Achim and Lepage, 2005, Ongur et al., 2006, Ragland et al., 2004, Thermenos et al., 2007, Leube et al., 2003).
In the present study we investigated the effect of G72 genotype on brain activity (as assessed by functional magnetic resonance imaging, fMRI) in a large sample of healthy subjects during long-term memory encoding and retrieval tasks. Memory tasks were chosen for several reasons. First, they strongly engage MTL structures, making it possible to test the hypothesis that G72 genotype had a measurable impact on brain activity of hippocampus and parahippocampus already in healthy controls. Second, the tasks tap into memory processes that are compromised in patients with schizophrenia (Heinrichs and Zakzanis, 1998, Aleman et al., 1999) and, to a lesser extent, patients with affective disorders (Sweeney et al., 2000). These memory deficits have been found to be associated with genetic vulnerability (e.g. Goldberg et al., 2006), making them promising endophenotypes, that is mediators between genotype and clinical phenotype (Gottesman and Gould, 2003).
Section snippets
Subjects
The subjects were recruited through postings at the University of Aachen, advertisements in local newspapers and an e-mail sent to all students of the University of Aachen. 83 subjects (56 men) were included in the present study. Inclusion criteria were age (18–55 years), right-handedness (as assessed by the Edinburgh Inventory, Oldfield, 1971), no psychiatric disorders according to ICD-10 and Western- or Middle European descent. The subjects' characteristics are given in Table 1. After a
Behavioural data
Analyses of behavioural data of the fMRI task (i.e. the number of correctly remembered faces in the retrieval session) revealed no significant differences in task performance between groups (F = 0.045, p = 0.956).
FMRI data
In a first step, memory activation (encoding > baseline, retrieval > baseline) as well as “deactivation” (baseline > encoding, baseline > retrieval) was calculated for the whole fMRI sample. During encoding, subjects activated a widespread network, with the main activation clusters encompassing
Discussion
In the present study we investigated the effect of G72 genotype on brain activity during a memory encoding and retrieval task in a large sample of healthy subjects. Based on previous neuroimaging studies on the neural correlates of schizophrenia and bipolar disorders as well as on previous genetic imaging studies both in controls and patients, we specifically predicted an effect of G72 on brain activity in the MTL. Contrary to our hypothesis however, we did not find brain activation differences
Conclusion
In conclusion, despite a large sample of subjects and a strong a-priori hypothesis we could not demonstrate an impact of G72 genotype on MTL brain activity in the domain of episodic memory encoding and retrieval. We believe that it is of great importance to report “negative” findings, especially in the field of genetic imaging where exploratory strategies are commonly applied. Furthermore, reporting “alternative” findings will limit the publication bias that occurs if only positive findings are
Acknowledgments
This work was supported by the Federal Ministry of Education and Research (Brain Imaging Centre West, 01GO0204).
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Both authors contributed equally.