Topographic projection is a general feature of brain architecture, and appears to be critical for appropriate coding and processing of information. The hippocampus and septum, which have been the focus of intense interest, since these structures play a central roles in learning and memory, are interconnected topographically. Although their topographic connections have been known for nearly two decades, and the topography may be critical for cognitive functions, the molecular basis for the topographic projection is unknown. 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 pre-synaptic and postsynaptic neurons. Consistent with this proposal, we have shown that Bsk, an eph family receptor, and its ligands are expressed in complementary gradients in the hippocampus and the target, lateral septum in the adult brain. Furthermore, we have shown that, one of the ligands, Elf-1, selectively inhibited the growth of topographically incorrect but allowed the growth of hippocampal neurites. These observations led to the hypothesis that eph family receptors and ligands serve as chemoaffinity labels for the hippocamposeptal topographic mapping. Several predictions can be made based on this hypothesis: 1, the eph family ligands and receptors are expressed in proper gradients at the time of topographic mapping; 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, we propose 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 additions, as critical tests for the roles of expression gradients of the eph molecules, we plan to take two complementary approaches to alter Bsk expression and function in vivo. First, we will inject a soluble eph ligand, A1-1/rags, which serves as an inhibitor for Bsk or related receptors, into developing mouse brains; Second, we will over-express Bsk using Talpha1 neuron-specific tubulin promoter, which generates high levels of uniform expression, in transgenic mice. The effect of these alterations on the hippocamposeptal 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 the mechanism of learning and memory, as well as diseases affecting these processes.
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