Neurogenesis, a process first thought to be limited to the prenatal period, occurs throughout life in distinct brain regions, such as the subventricular zone and the dentate gyrus subgranular zone. Over the past decade, a considerable amount of data has been accumulated regarding the identification, isolation, propagation and pluripotency of neural progenitor cells. However, little is known about the specific mechanisms that commit differentiation of progenitor cells toward a specific cell lineage, such as the neuronal or glial lineage. We propose to investigate the role of electrical activity in neural progenitor cell proliferation, differentiation and circuit formation, addressing our questions specifically to the dentate gyrus progenitor cell population. Our hypothesis is that electrical activity drives differentiation of dentate progenitor cells into the neuronal lineage, acting through fine modulation of glutamate receptor expression and activation. We propose to study these mechanisms in the adult organotypic hippocampal slice culture using transgenic mice that help us to identify the specific cell populations, electrophysiology to identify the profiles of undifferentiated and differentiated cells and two-photon microscopy to monitor morphological changes associated with electrical stimulation. Our objectives have a direct impact on the therapeutic use of neural progenitor cells in a variety of neurological disorders. An ability to identify specific factors that influence the differentiation of neural progenitor cells in vivo should provide us with important insights into the potential for endogenous and exogenous activation of progenitor cells, neurogenesis and the utility of dentate progenitor cells as agents for brain tissue reorganization and repair.
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