ROLE OF GROWTH FACTORS IN BRAIN DEVELOPMENT

We hypothesize that astrocytes, through their production of trophic molecules, play an active role in the development and perhaps maintenance of proximate neurons. Moreover, neuronal and hormonal signals of the local environment enhance this trophic capacity. We propose that this ability to support neurons is initiated during prenatam life, influencing neuronal survival and the development of mature function. Previous work in our tab supports this possibility. We focused on examination of astrocytes cultured from the basal forebrain and cortex, regions with well-characterized neuronal responses to neurotrophins, NGF, BDNF and NT-3. Astrocytes of these regions were found to express NGF, BDNF and NT-3; expression was regulated developmentally. Neurotrophins were highly expressed by cultured astrocytes derived from the fetus, but declined dramatically in astrocytes derived from the adult. Moreover, this expression was differentially regulated by the local neural signals, glutamate and acetylchotine, and, perhaps surprisingly, by estradiol. Estradiol binding sites as well as estrogen receptors a and b were detected on the cultured cells. Therefore, our culture studies suggest that astrocytes produce factors that support neurons and, further, that they are influenced by neurotransmitters and estrogen to do so optimally. To extend these studies we now propose to 1) evaluate neurotrophin expression in astroytes developing in vivo, 2) determine the biological actions of astrocyte-dedved neurotrophins on function and/or survival of nearby neurons, and 3) identify signaling cascades that underlie neuronal and hormonal signaling to astrocyles. These studies that evaluate the roles of astrocytes will provide insights with which to optimize the maintenance of the critical BF, HI and cortical regions that degenerate in such diseases as Alzheimer's dementia.