How to Cite this Article: Zubenko GS, Hughes III HB. 2011. Replacement of Homologous Mouse DNA Sequence With Pathogenic 6-Base Human CREB1 Promoter Sequence Creates Murine Model of Major Depressive Disorder. Am J Med Genet Part B 156:517–531.
Replacement of homologous mouse DNA sequence with pathogenic 6-base human CREB1 promoter sequence creates murine model of major depressive disorder†
Article first published online: 19 MAY 2011
Copyright © 2011 Wiley-Liss, Inc.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
Volume 156, Issue 5, pages 517–531, July 2011
How to Cite
Zubenko, G. S. and Hughes, H. B. (2011), Replacement of homologous mouse DNA sequence with pathogenic 6-base human CREB1 promoter sequence creates murine model of major depressive disorder. Am. J. Med. Genet., 156: 517–531. doi: 10.1002/ajmg.b.31197
- Issue published online: 10 JUN 2011
- Article first published online: 19 MAY 2011
- Manuscript Accepted: 14 APR 2011
- Manuscript Received: 25 JAN 2011
- The National Institute of Mental Health. Grant Number: MH47346
- National Center for Research Resources (NCRR). Grant Number: UL1 RR024153
- The National Institutes of Health. Grant Number: P41EB001977
- animal model
Major depressive disorder (MDD) is a leading cause of disability worldwide. Families with recurrent, early-onset MDD (RE-MDD), a severe, familial form of MDD, have provided an important resource for identifying and characterizing genetic variants that confer susceptibility to MDD and related disorders. Previous studies identified a rare, highly penetrant A(-115)G transition within the human CREB1 promoter that reduced promoter activity in vitro and was associated with depressive disorders in RE-MDD families. The development of an etiology-based recombinant animal model for MDD would facilitate the advancement of our limited understanding of the pathophysiology of MDD, as well as the development of improved treatments. Here we report the construction and initial characterization of a congenic mutant C57BL/6NTac mouse model that carries the human pathogenic sequence at the homologous position of the mouse Creb1 promoter. The recombinant strain exhibited decreases in reproductive capacity and pup survival that may be related to increased infant mortality observed in RE-MDD families; enlargement of the cerebral ventricles; reduced levels of CREB protein in the mouse cerebral cortex, as predicted from transfection experiments employing the pathogenic human CREB1 promoter; and alterations in two standardized behavioral tests, the forced swim and marble burying tests. These initial findings support the pathogenicity of the human A(-115)G promoter variant, and invite further characterization of this etiology-based recombinant animal model for MDD. Human promoter variants that have highly penetrant effects on disease expression provide an attractive opportunity for creating etiology-based mouse models of human diseases, with minimal disruption of the mouse genome. © 2011 Wiley-Liss, Inc.