Nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, neurotrophin-4, and neurotrophin-5 are members of a family of proteins (the neurotrophins) that promote the normal differentiation, growth, and survival of peripheral and central nervous system neurons. These factors have attracted immense scientific and clinical interest because of their implication in the pathogenic mechanisms of Alzheimer's disease, stroke, epilepsy, and aging. A better understanding of the normal function of these proteins in the nervous system may lead to new therapeutic approaches to neurologic disease. In this proposal, we will study the effects of nerve growth factor, brain- derived neurotrophic factor, neurotrophin-3, neurotrophin-4, and neurotrophin-5 on neuronal mitogenesis, differentiation, and survival in the rate hippocampus. The rat hippocampus is an ideal model for the study of central nervous system development because it is one of the best- characterized regions of the brain in terms of its development, connectivity, neurochemistry, and physiology. We have also chosen to study the hippocampus because it is a region of the brain that is especially vulnerable to a variety of disease processes, including neuronal degeneration and aberrant dendritic outgrowth as seen in Alzheimer's disease and intractable epilepsy. In the first phase of our experiments, we will construct a detailed developmental map of the receptors for the neurotrophins (the trk family of tyrosine kinases) in the rat hippocampus. We will correlate the cellular expression of trk receptors with precisely-timed developmental events -- neuronal mitogenesis, differentiation, migration, and synaptogenesis -- in order to identify putative developmental functions for the trk receptors in the central nervous system. We will use antibodies raised against high- conserved, hydrophilic domains of the trk proteins and standard avidin- biotin immunohistochemistry in order to visualize neurons expressing trk receptors. The mitogenic effects of nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, neurotrophin-4, and neurotrophin-5, will be tested in cultured preparations of hippocampal precursors using thymidine incorporation and bromodeoxyuridine labeling. Next, we will study the effects of these growth factors on the differentiation of hippocampal precursors into Ammon's horn pyramidal neurons, dentate granule cells, and intrinsic interneurons. Selective antibody markers will be used to distinguish between subclasses of neurons. Finally, we will study the effects of these growth factors on neuronal survival and morphology in hippocampal culture. Subclasses of neurons (pyramidal and dentate granule cells, interneurons) will again be distinguished using selective antibody markers. Dendritic elongation and branching, changes in axonal extension and perikaryal size will be studied.
| Eide, F F; Vining, E R; Eide, B L et al. (1996) Naturally occurring truncated trkB receptors have dominant inhibitory effects on brain-derived neurotrophic factor signaling. J Neurosci 16:3123-9 |
| Eide, F F; Lowenstein, D H; Reichardt, L F (1993) Neurotrophins and their receptors--current concepts and implications for neurologic disease. Exp Neurol 121:200-14 |
