Putting the Brakes on Proliferation: Gene Dosage Effects on Hippocampal Neurogenesis in the Ts65Dn Mouse Model of Down Syndrome
AuthorClark, Sarah Michelle
AdvisorYarowsky, Paul J.
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AbstractAs the most prevalent genetic cause of intellectual disability in the western world, Down syndrome (DS) presents a variety of challenges. This is especially true for the aging DS population, which is facing the reality that virtually all individuals who survive to their fifth decade will develop Alzheimer's disease. Thus, it has become imperative to identify and understand underlying mechanisms that can potentially contribute to cognitive impairments in DS. Given that most of the cognitive deficits in DS have been associated with hippocampal dysfunction and that neurogenesis in the adult hippocampus contributes to cognitive processing, the goal of our research was to determine whether adult hippocampal neurogenesis is impaired in the hippocampi of a mouse model of DS, Ts65Dn. Results presented herein demonstrate that neurogenesis is significantly (~50%) reduced in the subgranular zone (SGZ) of the dentate gyrus of adult male Ts65Dn mice. The use of the thymidine analog 5'-Bromo-2-deoxyuridine (BrdU) and cell-type specific markers led us to conclude that a significantly large proportion of the neuroprogenitor population resident within the SGZ fails to proliferate. The consequence of reduced cell proliferation is a significant deficit in the production of new neurons in the dentate gyrus, which may ultimately impinge upon hippocampal function. Gene overexpression in DS may contribute to cell cycle alterations within the neuroprogenitor population via dysregulation of signaling pathways required for neurogenesis and through the overproduction of reactive oxygen species (ROS), which negatively impact cell viability. Our research has established that chronic treatment with the antidepressant fluoxetine rescues impaired neurogenesis, increasing cell proliferation to control levels. Additionally, we have shown that treatment with the antioxidant curcumin can be neuroprotective through the reduction of oxidative damage, which in turn facilitates the generation of new neurons. Ultimately, we have identified a mechanism that can contribute to hippocampal dysfunction in DS and have established that dysregulation of neurogenesis can be remedied using pharmacological therapies already available, thus, providing hope for future treatments.
DescriptionUniversity of Maryland, Baltimore. Pharmacology and Experimental Therapeutics. Ph.D. 2011
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/506
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