ABSTRACT
The cytokine transforming growth factor ß1 (TGFß1) 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 TGFß1 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 TGFß1 in isolation, we used transgenic mice that over-express a constitutively active porcine TGFß1 in astrocytes. We found that TGFß1 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 TGFß1 over-expressing mice. Together, our data indicate that chronic upregulation of TGFß1 negatively impacts hippocampal structure and, even in the absence of disease, impairs hippocampus-dependent learning.
