ROLE OF GROWTH FACTORS IN BRAIN DEVELOPMENT

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The classic neurotrophin theory holds that distant targets provide survival factors to innervating neurons. However, we have found that local support cells may also be sources of these molecules. The current project uses the basal-forebrain medial septum (BF) as a critical model to explore the proposal that local neuron-astrocyte-neuron regulatory loops support survival and function of specific brain regions during development and maturity. Preliminary studies examining cultured BF neurons and astrocytes are the basis for the proposed work. We found that individual BF neural signals differentially regulate BF astrocytic gene expression of the neurotrophins, NGF, BDNF and NT3. These neurotrophins, in turn, differentially influence BF neuron survival, neurite extension and function, and, in related studies, regulate synaptic transmission and astrocyte morphology. To investigate the role of neuron-astrocyte-neuron regulatory loops we will 1) examine astrocyte development in the absence of BF neurons, 2) define regulation of astrocytes by neural signals, 3) evaluate autocrine regulation by neurotrophines, 4) compare astrocytes derived from embryonic day 17 to cells derived from postnatal day 1 and adults to define stage-specific astrocyte function, and 5) define physiologic consequences of mechanisms identified in culture by delineating the effects of the aforementioned neural signals and trophins on E17, P1 and adult BF in vivo. These studies are designed to explore local neuron-astrocyte-neuron regulation in the developing and mature BF. An understanding of this regulation will provide insights for optimization of survival and function of BF, a region that degenerates in Alzheimer's disease.