Original Article | Published:

Neuroanatomical phenotypes in a mouse model of the 22q11.2 microdeletion

Molecular Psychiatry volume 19, pages 99107 (2014) | Download Citation

Abstract

Recurrent deletions at the 22q11.2 locus have been established as a strong genetic risk factor for the development of schizophrenia and cognitive dysfunction. Individuals with 22q11.2 deletions have a range of well-defined volumetric abnormalities in a number of critical brain structures. A mouse model of the 22q11.2 deletion (Df(16)A+/−) has previously been utilized to characterize disease-associated abnormalities on synaptic, cellular, neurocircuitry, and behavioral levels. We performed a high-resolution MRI analysis of mutant mice compared with wild-type littermates. Our analysis revealed a striking similarity in the specific volumetric changes of Df(16)A+/− mice compared with human 22q11.2 deletion carriers, including in cortico-cerebellar, cortico-striatal and cortico-limbic circuits. In addition, higher resolution magnetic resonance imaging compared with neuroimaging in human subjects allowed the detection of previously unknown subtle local differences. The cerebellar findings in Df(16)A+/− mice are particularly instructive as they are localized to specific areas within both the deep cerebellar nuclei and the cerebellar cortex. Our study indicates that the Df(16)A+/−mouse model recapitulates most of the hallmark neuroanatomical changes observed in 22q11.2 deletion carriers. Our findings will help guide the design and interpretation of additional complementary studies and thereby advance our understanding of the abnormal brain development underlying the emergence of 22q11.2 deletion-associated psychiatric and cognitive symptoms.

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Acknowledgements

We thank Louise van der Weerd for helpful discussions during the initial phase of this project and Christine LaLiberté, Kim Stark and Matthijs van Eede for their assistance with aspects of the MRI scanning and analysis. We would also like to acknowledge the Ontario Mental Health Foundation (OHMF) for salary support (JE). This work was supported by grants from the US National Institute of Mental Health, Grants MH67068 (to MK and JAG) and MH077235 (to JAG) and the Canadian Institute for Health Research (CIHR) and the Ontario Brain Institute (OBI).

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Author notes

    • J Ellegood
    •  & S Markx

    These authors contributed equally to this work.

Affiliations

  1. Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada

    • J Ellegood
    • , J P Lerch
    • , P E Steadman
    •  & R M Henkelman
  2. Department of Psychiatry, Columbia University Medical Center, New York, NY, USA

    • S Markx
    •  & M Karayiorgou
  3. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    • J P Lerch
    • , P E Steadman
    •  & R M Henkelman
  4. Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands

    • C Genç
    •  & S A Kushner
  5. Department of Biomedical Engineering, Columbia University Medical Center, New York, NY, USA

    • F Provenzano
  6. Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, NY, USA

    • J A Gogos
  7. Department of Neuroscience, Columbia University Medical Center, New York, NY, USA

    • J A Gogos

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Competing interests

The authors declare no conflict of interest.

Corresponding authors

Correspondence to M Karayiorgou or J A Gogos.

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https://doi.org/10.1038/mp.2013.112

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

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