Alterations of brain anatomy in mouse model of MDD created by replacement of homologous mouse DNA sequence with an illness-associated 6-base human CREB1 promoter sequence

Authors

  • George S. Zubenko,

    Corresponding author
    1. Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
    2. Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, Pennsylvania
    • Correspondence to:

      George S. Zubenko, M.D., Ph.D., WPIC, 14th Floor, 3811 O'Hara Street, Pittsburgh, PA 15213.

      E-mail: zubenkog@pitt.edu

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  • Hugh B. Hughes,

    1. Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • T. Kevin Hitchens,

    1. Pittsburgh NMR Center for Biomedical Research, Carnegie Mellon University, Pittsburgh, Pennsylvania
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  • Bruce M. Cohen

    1. Harvard Medical School, Boston, Massachusetts
    2. Frazier Research Institute, McLean Hospital, Belmont, Massachusetts
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ABSTRACT

We have recently reported the creation and initial characterization of an etiology-based recombinant mouse model of a severe and inherited form of Major Depressive Disorder (MDD). This was achieved by replacing the corresponding mouse DNA sequence with a 6-base DNA sequence from the human CREB1 promoter that is associated with the development of MDD in men and women from families identified by probands with recurrent, early-onset MDD (RE-MDD). Individuals in these families are also at increased risk for childhood developmental disorders and late life neurodegenerative disorders. The current study used three-dimensional magnetic resonance microscopy (3D-MRM) to determine the effect of the resulting humanized mutation of the mouse Creb1 gene on the anatomy of the mouse brain. Homozygous mutant mice manifested prominent increases in the volume and surface area of the lateral ventricles, as well as reduced volume of the anterior corpus callosum, compared to age/sex-matched wild-type mice. No significant genotype effects were observed on the volume or surface area of total brain, or several brain regions sometimes observed to be abnormal in human depression, including hippocampus, amygdala, or striatum. These findings suggest that at least some forms of MDD result from abnormal brain development produced by inherited genetic variants. © 2013 Wiley Periodicals, Inc.

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