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Effect of disrupted-in-schizophrenia-1 on pre-frontal cortical function

Molecular Psychiatry volume 13, pages 915–917 (2008)Cite this article

Several linkage and genetic association studies have implicated the disrupted-in-schizophrenia-1 (DISC1) gene as influencing susceptibility to schizophrenia, and bipolar disorder,1 but relatively little is known about its effect on brain function. DISC1 is expressed in centrosomes, mitochondria, the cytoplasm of postsynaptic spines, and actin stress fibers of cerebral cortical neurons.1 It interacts with proteins involved in cell division, cytoskeletal organization and intracellular transport, including PDE4B, which has been linked to learning and memory, and Ndel1, a key regulator of neuronal migration and a putative target of anti-psychotic drugs.1 Knockdown of DISC1 perturbs neurite outgrowth in vitro,1, 2 and cortical neuronal migration and dendritic arborization in vivo.1 Over-expression of DISC1 leads to enhanced neurite growth in vitro,1 whereas expression of mutant human DISC1 in mice is associated with behavioural abnormalities, ventricular enlargement and attenuation of cortical neurite outgrowth.3

Abnormal pre-frontal function is a robust pathophysiological feature of psychotic disorders, and may underlie many of the associated symptoms and cognitive deficits.4 A risk gene for these disorders would therefore be expected to influence pre-frontal function. We used functional neuroimaging to test the hypothesis that DISC1 would significantly influence pre-frontal function in healthy volunteers. Functional magnetic resonance imaging was employed to measure regional brain activation during a verbal fluency task, a classical test of pre-frontal function which requires the generation of words from letter cues.5 Execution of this task is normally associated with prominent pre-frontal activation, particularly in the left hemisphere.5 In patients with psychotic disorders, task performance is impaired and pre-frontal activation is altered.4 We scanned 53 healthy volunteers consisting of 27 Cys704 carriers (including 7 Cys704 homozygotes) and 26 Ser704 homozygotes (Supplementary Table S1; Supplementary Materials and Methods). Demographic features (intelligence quotient, years of education, gender, handedness and ethnicity) were not different between genotype groups (at P<0.05) except for age (F=4.27, P=0.044) which was therefore used as a covariate of no interest. Subjects articulated responses out loud, permitting on-line recording of task performance. We selected the Ser704Cys polymorphism, encoded by the rs821616 single-nucleotide polymorphism (SNP), as this coding and non-synonymous SNP is the only one that has been shown to have a functional impact at the molecular level.6 Furthermore, in genetic association studies the Ser704Cys polymorphism has been associated with schizophrenia,7 whereas neuroimaging studies suggest that it has effects on the structure or function of brain regions that have been implicated in psychotic disorders, such as the frontal white matter,6 the anterior cingulate gyrus,6 and the hippocampus.8

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References

  1. Porteous DJ, Thomson P, Brandon NJ, Millar JK . Biol Psychiatry 2006; 60: 123–131.

    Article  CAS  Google Scholar 

  2. Duan X, Chang JH, Ge S, Faulkner RL, Kim JY, Kitabatake Y et al. Cell 2007; 130: 1146–1158.

    Article  CAS  Google Scholar 

  3. Pletnikov MV, Ayhan Y, Nikolskaia O, Xu Y, Ovanesov MV, Huang H et al. Mol Psychiatry 2008; 13: 173–186.

    Article  CAS  Google Scholar 

  4. Gur RE, Keshavan MS, Lawrie SM . Deconstructing psychosis with human brain imaging. Schizophr Bull 2007; 33: 921–931.

    Article  Google Scholar 

  5. Fu CH, Morgan K, Suckling J, Williams SC, Andrew C, Vythelingum GN et al. Neuroimage 2002; 17: 871–879.

    Article  Google Scholar 

  6. Hashimoto R, Numakawa T, Ohnishi T, Kumamaru E, Yagasaki Y, Ishimoto T et al. Hum Mol Genet 2006; 15: 3024–3033.

    Article  CAS  Google Scholar 

  7. Callicott JH, Straub RE, Pezawas L, Egan MF, Mattay VS, Hariri AR et al. Proc Natl Acad Sci USA 2005; 102: 8627–8632.

    Article  CAS  Google Scholar 

  8. Cannon TD, Hennah W, van Erp TG, Thompson PM, Lonnqvist J, Huttunen M et al. Arch Gen Psychiatry 2005; 62: 1205–1213.

    Article  CAS  Google Scholar 

  9. Winterer G, Weinberger DR . Trends Neurosci 2004; 27: 683–690.

    Article  CAS  Google Scholar 

  10. Szeszko PR, Hodgkinson CA, Robinson DG, Derosse P, Bilder RM, Lencz T et al. Biol Psychol 2007; e-pub ahead of print.

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Authors and Affiliations

  1. Division of Psychological Medicine and Psychiatry, Section of Neuroimaging, Institute of Psychiatry, King's College London, London, UK

    D P Prata, A Mechelli, C H Y Fu, M Picchioni, F Kane, S Kalidindi, T Toulopoulou, A Miorelli, R Murray & P K McGuire

  2. Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK

    D P Prata, E Kravariti & D A Collier

  3. Department of Psychology, Institute of Psychiatry, King's College London, London, UK

    A Mechelli & S Kalidindi

  4. Department of Psychiatry, Clinical Science Institute, National University of Ireland, Galway, Ireland

    C McDonald

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  1. D P Prata
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Correspondence to D P Prata.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Prata, D., Mechelli, A., Fu, C. et al. Effect of disrupted-in-schizophrenia-1 on pre-frontal cortical function. Mol Psychiatry 13, 915–917 (2008). https://doi.org/10.1038/mp.2008.76

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