The long term goal of this study is to elucidate the molecular mechanisms of axonal targeting in the hippocamposeptal system. It has been proposed by Roger Sperry that topographic mapping is accomplished by matching gradients of chemoaffinity labels on the presynaptic and postsynaptic neurons. Consistent with this proposal, the pirncipal investigator has shown that Bsk, an eph family receptor, and its ligand are expressed in complementary gradients in the hippocampus and the target, lateral septum in the adult brain. Furthermore, he has shown one of these ligands, Elf-1, selectively inhibited the growth of topographically incorrect neurites, but allowed the growth of correct hippocampal neurites. These observation sled to the hypothesis that eph family receptors and ligands serve as chemoaffinity labels for the hippocamposeptal topograph mapping. Several predictions can be made based on this hypothesis: 1) the eph family ligands and receptors are expressed in propoer gradients at the time of topographic maping; 2) the ligands inhibit or support the growth of axons from appropriate regions of the hippocampus in vitro; 3) changing the gradients of expression disturbs the topographic projection in vivo. To test these predictions, the investigator proposed to examine the spatial and temporal patterns of expression of eph ligands and receptors in the hippocamposeptal system and study the biological actions of the ligands on the hippocampal neurons in vitro. In addition, as critical tests for the roles of expression gradients of the eph molecules, the applicant plans to take two complementary approaches to alter Bsk expression and function in vivo. First, he will inject a soluble eph ligand, A1-1/RAGS, which serves as an inhibitor for Bsk or related receptors, into developing mouse brain. Second, he will overexpress Bsk using Talphal neuron-specific tublin promoter, which generates high levels of uniform expression, in transgenic mice. The effects of these alterations on the hippocampal topographic projection will be examined using axonal tracing techniques. These studies will help to understand how the output pathways of the hippocampus are organized and may shed light on mechanisms of learning and memory, as well as diseases affecting these processes.
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