Chronic over-expression of TGFβ1 alters hippocampal structure and causes learning deficits

Authors

  • Alonso Martinez-Canabal,

    1. Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada
    2. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
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  • Anne L. Wheeler,

    1. Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada
    2. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
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  • Dani Sarkis,

    1. Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada
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  • Jason P. Lerch,

    1. Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada
    2. Department of Medical Biophysics, University of Toronto, 610 University Ave., Toronto, Ontario, Canada
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  • Wei-Yang Lu,

    1. Molecular Brain Research Group, Robarts Research Institute, University of Western Ontario, London, Ontario, Canada
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  • Marion S. Buckwalter,

    1. Department of Neurology and Neurological Sciences, Stanford University, Stanford, California
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  • Tony Wyss-Coray,

    1. Department of Neurology and Neurological Sciences, Stanford University, Stanford, California
    2. Center for Tissue Regeneration, Repair, and Restoration, Veterans Administration Palo Alto Health Care Systems, Palo Alto, California
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  • Sheena A. Josselyn,

    1. Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada
    2. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
    3. Department of Physiology, University of Toronto, Toronto, Ontario, Canada
    4. Department of Psychology, University of Toronto, Toronto, Ontario, Canada
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  • Paul W. Frankland

    Corresponding author
    1. Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada
    2. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
    3. Department of Physiology, University of Toronto, Toronto, Ontario, Canada
    4. Department of Psychology, University of Toronto, Toronto, Ontario, Canada
    • Correspondence to: Paul W. Frankland, Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON M5G 1X8 Canada. E-mail: paul.frankland@sickkids.ca

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ABSTRACT

The cytokine transforming growth factor β1 (TGFβ1) is chronically upregulated in several neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jacob disease, amyotrophic lateral sclerosis and multiple sclerosis, and following stroke. Although previous studies have shown that TGFβ1 may be neuroprotective, chronic exposure to elevated levels of this cytokine may contribute to disease pathology on its own. In order to study the effects of chronic exposure to TGFβ1 in isolation, we used transgenic mice that over-express a constitutively active porcine TGFβ1 in astrocytes. We found that TGFβ1 over-expression altered brain structure, with the most pronounced volumetric increases localized to the hippocampus. Within the dentate gyrus (DG) of the hippocampus, increases in granule cell number and astrocyte size were responsible for volumetric expansion, with the increased granule cell number primarily related to a marked reduction in death of new granule cells generated in adulthood. Finally, these cumulative changes in DG microstructure and macrostructure were associated with the age-dependent emergence of spatial learning deficits in TGFβ1 over-expressing mice. Together, our data indicate that chronic upregulation of TGFβ1 negatively impacts hippocampal structure and, even in the absence of disease, impairs hippocampus-dependent learning. © 2013 Wiley Periodicals, Inc.

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