DISConnectivity in schizophrenia (Commentary on Di Giorgio et al.)

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Despite many years of research the causes of schizophrenia have remained, to quote Winston Churchill, ‘a riddle wrapped in a mystery inside an enigma’. Recent advances in the genetics of schizophrenia provide some hope for decoding this enigma. The gene DISC1 (Disrupted In SChizophrenia 1) is one of the best supported genetic risk factors for schizophrenia (Porteous et al., 2006). A balanced translocation disrupting this gene is associated with mental illness in a large family in Scotland, and subsequent studies have shown genetic association of DISC1 and interacting proteins with schizophrenia in a wide range of populations (Porteous et al., 2006). However how genetic variation in DISC1 affects the brain to cause susceptibility for mental illness is still far from fully clear.

In this issue, Di Giorgio et al. (2008) address this question by studying the effect of a common polymorphism in the DISC1 gene (Ser704Cys), previously associated with increased risk for the disorder, on brain structure and function using MRI scanning (Callicott et al., 2005). A large number of healthy control volunteers underwent MRI scans in this study to examine both brain structure and brain function using a scene memory task. In the latter task subjects viewed a series of scenes which they were later asked to recognise. Previous studies have shown that encoding memories for such scenes is associated with activation of the hippocampus and prefrontal cortex (PFC) regions including the dorsolateral PFC, both brain regions implicated in the pathogenesis of schizophrenia.

Participants were genotyped for the DISC1 Ser704Cys polymorphism and the genotype groups were compared in terms of the MRI measures. Di Giorgio et al. (2008) found that Ser/Ser homozygous subjects had relatively increased volume of the the hippocampal formation, a key brain region involved in memory. In addition Ser/Ser subjects showed increased activation of the hippocampus during the scene memory task. Perhaps most strikingly however Di Giorgio et al. (2008) also showed that Ser704Cys status affected the integration of activity between the hippocampus and the prefrontal cortex during memory encoding, using a technique called Psycho-Physiological Interaction analysis. Specifically they found that Ser/Ser subjects showed greater functional integration of the hippocampus and the dorsolateral PFC.

These results strongly suggest that genetic variation in DISC1 can contribute to risk for schizophrenia by altering hippocampal formation structure and function. This finding is particularly convincing because DISC1 is heavily expressed in the hippocampus during development, and is known to interact with other proteins involved in memory formation (Porteous et al., 2006). However the present results also support the view that the symptoms of schizophrenia do not arise simply from deficits in the function of a single brain region, but are more generally related to altered interactions between different neural structures (Friston, 1998). An important challenge for future genetic imaging studies in schizophrenia is therefore to use techniques such as those employed by Di Giorgio et al. (2008) to investigate the effect of susceptibility genes for schizophrenia on structural and functional connectivity between brain regions.

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