The postnatal subventricular zone (SVZ) is a germinal center composed of a network of chains of migrating and proliferative neuroblasts ensheathed by glial fibrillary acidic protein immunopositive (GFAP+) cells, which display the characteristics of stem cells. The progenitors migrate throughout the SVZ and along the rostral migratory stream (RMS) toward the olfactory bulb where they continuously replace interneurons throughout life. Identifying the signals influencing the behavior of SVZ progenitors would lead to a better basic understanding of the mechanisms influencing replacement of olfactory bulb interneurons, and is necessary to design strategies to promote neurogenesis and self-repair. The production of progenitors is thought to be regulated by molecules providing communication signals between neuroblasts and GFAP+ cells, yet our knowledge of such signaling remains rudimentary. The central hypothesis of this grant is that glutamatergic signaling from GFAP+ cells to neuroblasts balances GABA's inhibitory function by promoting the proliferation of postnatal SVZ progenitors.
Three aims will be addressed. First we will determine whether a fast glutamatergic signaling from GFAP+ cells to neuroblast exists. As neuroblasts signal to GFAP+ cells via GABAergic signaling, glutamatergic signaling would provide a feedback loop necessary for a bidirectional communication between these two cell types. Second, we will determine whether PGE2 released from SVZ cells modulates glutamate release from GFAP+ cells and thus mGluR activation. Finally, we will determine whether glutamate and PGE2's modulation of glutamate release provide a positive control on cell proliferation to counterbalance GABA's inhibitory influence. We will use patch-clamp and Ca2+ imaging techniques, and perform proliferation assays in brain slices and in vivo. We will use CD1 mice and several lines of transgenic mice to address our aims. It is hoped that together the proposed experiments will identify the existence and function of a bidirectional communication between GFAP+ cells and neuroblasts, and further our understanding of how intercellular signaling regulates postnatal neurogenesis. ? ?
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