The immediate goal of this proposal is to understand the role of nerve growth factor (NGF) in the development of afferent connections to the rat hippocampus and neocortex. The studies are based on the general hypothesis that NGF acts through a similar mechanism in both the developing and adult brain to permit selective stabilization of axon collaterals and synapses in response to experience. We will use immunocytochemical localization of NGF (with an affinity-purified antibody) and receptors for NGF (NGF-R), using monoclonal antibody 192 IgG, to test three specific hypotheses: first, that axons of basal forebrain neurons contain NGF-R very early in development, and that their growth may be guided by the early presence of NGF protein in the hippocampus and cortex. Secondly, we propose that NGF-R and NGF may be expressed transiently in central sensory pathways during initial outgrowth of axons and during synaptic stabilization within the respective target regions, and may act to increase the local concentration gradient of NGF, thereby playing a role in guiding axon outgrowth and influencing the specificity of thalamo-cortical connections. Thirdly, we propose to test the hypothesis that NGF-R and NGF are concentrated on glial cell surfaces within the path along which granule cell neuronal migration to reach the dentate anlage, and thus may play a role in guiding neuronal migration in the developing hippocampus. We will also use light and electron microscopic (EM) techniques to colocalize NGF-R or NGF protein and either vimentin or glial fibrillary acidic protein (GFAP) immunoreactivity in retina, optic tract, lateral geniculate nucleus and visual cortex and in the hippocampal formation of the rat to determine (a) which cells and processes (neuronal or glial) are immunoreactive for NGF and NGF-R; (b) how the distribution of NGF and NGF-R changes as a function of age, and (c) how the presence of NGF and NGF-R in the sensory and hippocampal systems correlates with the timing of neuronal migration, axon outgrowth, afferent arrival, synaptogenesis and modifiability by experience. The proposed studies are valuable, not only for understanding basic mechanisms controlling neuronal migration, axonal outgrowth and selective synaptogenesis, but for identifying the normal course of development of NGF and NGF receptors in sensitive CNS tissues, as a prelude to understanding the possible role of NGF dysfunction in neurological disorders such as familial dysautonomia, and in basal forebrain neuron loss associated with aging and Alzheimer's disease.
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