The effect of Neuregulin 1 on neural correlates of episodic memory encoding and retrieval
Introduction
During episodic memory processing, several brain regions are involved in encoding new material. Among these, the prefrontal cortex (PFC) and the medial temporal lobe structures such as the hippocampal formation, including the parahippocampal gyrus and the subiculum, are of major importance (Brewer et al., 1998, Cabeza and Nyberg, 2000, Fernandez and Tendolkar, 2001, Kircher et al., 2008, Wagner et al., 1998). Depending on the material type to be encoded, other cortical and sub-cortical structures such as the amygdala, the fusiform gyrus, or parietal regions are engaged (Cabeza and Nyberg, 2000, Fernandez and Tendolkar, 2001). The hippocampus is the key area implicated in the formation of item-item associations (Henke et al., 1997), while other regions such as the PFC support effortful associative processing strategies and suppress irrelevant information (Cabeza and Nyberg, 2000, Fernandez and Tendolkar, 2001).
Patients with schizophrenia show strong deficits in a variety of memory tasks, particularly in the verbal domain (Dickinson et al., 2007). Relatives of patients display similar deficits, albeit to a lower degree (e.g., Snitz et al., 2006). Meta-analytical findings suggest that patients with schizophrenia exhibit hypoactivations of the bilateral frontal gyri and the right hippocampus during memory tasks (Achim and Lepage, 2005). Interestingly, in the latter analysis, no regions were found that showed stronger activations in patients compared to controls. The neural correlates of memory encoding were also investigated in relatives of patients (for a meta-analysis see Macdonald et al., 2009). Even though there is a very limited amount of literature on relatives, two recent studies with subjects at high risk for schizophrenia showed prefrontal hyperactivations during encoding compared to subjects without elevated risk. However, performance did not differ between groups (Bonner-Jackson et al., 2007, Whyte et al., 2006). Thus, patients show prefrontal hypoactivations compared to healthy subjects while relatives of patients show hyperactivations when compared to subjects without elevated risk.
So far, several susceptibility genes for schizophrenia have been identified and replicated in independent studies. Among them are G72/G30 (e.g., Abou Jamra et al., 2006, Rietschel et al., 2008, Schumacher et al., 2004), DISC1 (Porteous et al., 2006) and Neuregulin 1 (NRG1, e.g., Stefansson et al., 2002). NRG1 is involved in several neurodevelopmental functions such as cell migration, myelination and receptor expression (Anton et al., 1997, Chen et al., 2006, Corfas et al., 2004, Falls, 2003, Ghashghaei et al., 2006, Hahn et al., 2006, Harrison and Law, 2006, Nave and Salzer, 2006). It could be shown that NRG1 is involved in long term potentiation and synaptic plasticity in the hippocampus (Kwon et al., 2008, Neddens et al., 2009). Besides its biological plausibility, the pathogenetic pathways remain unknown so far. Several single nucleotide polymorphisms (SNPs) of NRG1 have been associated with cognitive and anatomical phenotypes that are also found in patients compared to healthy controls. It has been shown that SNP8NRG243177 (rs6994992) has a significant influence on white matter density and integrity in healthy subjects (McIntosh et al., 2008), as well as on psychotic symptoms and neural correlates of a sentence completion task in high-risk subjects (Hall et al., 2006). Another SNP of NRG1 (SNP8NRG221533; rs35753505) has been found to be correlated with medial frontal fractional anisotropy (Winterer et al., 2008) as well as neural correlates of verbal fluency in healthy subjects (Kircher et al., 2009a) and patients with schizophrenia or bipolar disorder (Mechelli et al., 2008). In addition, this SNP has an effect on neural correlates of working memory in healthy subjects (Krug et al., 2008a) and in patients with schizophrenia (Kircher et al., 2009c).
It could be shown that prefrontal regions support both working memory and long term memory performance (Ranganath et al., 2003). As patients with schizophrenia exhibit deficits in both kinds of memory, it is of interest whether genetic variation in a susceptibility gene such as NRG1 significantly influences neural correlates of episodic memory in healthy individuals.
In this study the neural correlates of episodic memory encoding and retrieval were linked to NRG1 rs35753505 status in a large sample of healthy individuals. Based on studies on high-risk subjects (Bonner-Jackson et al., 2007, Wright et al., 2006) and the known role of NRG1 in the hippocampus (Kwon et al., 2008, Neddens et al., 2009), it was hypothesized that subjects carrying the minor alleles (for European populations: C) would exhibit hyperactivations in key areas of episodic memory processes such as the MTL and the PFC.
Section snippets
Subjects
This sample is a subsample of Kircher et al., 2009b, Krug et al., 2008a, Sheldrick et al., 2008). Subjects were recruited at RWTH Aachen University; the majority of them (90%) were students. Ninety-four subjects were enrolled into the study (66 men, 28 women). The inclusion criteria were age 18–55 years and no psychiatric disorder according to ICD-10 past or present. The subjects had a mean age of 23.2 years (SD = 2.9), were all right handed (as tested with the Edinburgh Laterality Scale (
Encoding task
During the encoding phase, either single pictures of neutral faces (encoding condition) or the symbol “#” (baseline condition) were presented on a black background for 4000 ms in a pseudo-randomized order using Presentation software package (Neurobehavioral Systems Inc., San Francisco, CA). Following this, stimuli were replaced by a blank screen for another 1000 ms completing one trial. During face encoding participants were instructed to actively memorize each face for later recognition. In
Genetic analysis
Resulting distribution of NRG1 rs35753505 was 34 with T/T genotype (22 male), 32 with T/C genotype (27 male) and 28 with C/C genotype (17 male). Characteristics of this sample are given in Table 1. Groups did not differ with regard to their status in genes which have previously been tested for the given phenotype in this sample (i.e., APO ɛ, rs1018381 of Dysbindin (DTNBP1), rs3918324 and rs1421292 of G72 or rs1006737 of CACNA1C).
Encoding
During the gender discrimination task which was only employed to
Encoding
In a first step, the whole-group contrast “ENCODING” revealed strong activations of the hippocampal formation bilaterally and the occipital cortex (Fig. 1).
In a second step, an ANOVA with genotype as factor revealed a strong linear effect of genotype with non-risk allele carriers exhibiting significantly lower activations in the fusiform gyri (bilaterally), the cingulate gyrus (BA 24), the left middle frontal gyrus (BA 9) and the left middle occipital gyrus (BA 19) (Fig. 2).
No decrease in
Discussion
In this study, the effect of NRG1 SNP8NRG221533 (rs35753505) carrier status on episodic memory encoding and retrieval was investigated in a large sample of healthy subjects (n = 94). We found a significant increase in brain activation mainly in the left middle frontal gyrus (BA 9), the cingulate cortex (BA 24) and the fusiform gyrus (bilaterally) during face encoding compared to baseline that was correlated with number of risk alleles. During retrieval, while there were differences in
Conclusion
In summary, we found that HAPICE related genetic variation (rs35753505) is related to brain activation mainly in the right anterior cingulate cortex, the left prefrontal cortex, left primary visual cortex and the fusiform gyrus bilaterally during episodic memory processes. It is hypothesized that the increased recruitment of prefrontal and fusiform areas and the ACC helps subjects of high-risk status to maintain task performance. Taken together our results with studies on patients with
Financial disclosure
All authors report no conflict of interest.
Acknowledgments
This work was supported by the Federal Ministry of Education and Research to T.K. (grant no. 01GO0204).
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