9808938 SCHACHER The formation of neural circuits during development is a multistep process involving axon guidance, target selection and synapse formation. The late stages of synapse formation include activity-dependent strengthening and stabilization of "behaviorally relevant" connections and the elimination of others. Neural circuits established during development continue to be modified in post-embryonic life by the environment and by the experience of an organism. These later modifications in the efficacy of connections can be short- or long-lasting, and can include structural changes such as the formation of new connections or the elimination of pre-existing ones. Some of the cellular and molecular mechanisms first utilized during development are likely to be used again in experience-dependent modifications of connections in the adult. In this project, a model in vitro system consisting of identified neurons isolated from the central nervous system of the marine mollusk Aplysia californica will be used to examine the role of cell surface molecules and local macromolecular synthesis on processes involved in synaptic modification at two stages: in competition-dependent synapse elimination during initial synapse formation, and in synapse elimination induced by neuromodulatory chemicals, which accompanies long-term synaptic depression in mature circuits after particular types of external stimulation. Isolated Aplysia neurons reliably form chemical connections in culture that express short- and long-term forms of synaptic plasticity known to accompany various form of simple learning in the organism. This model cell culture system will be used in combination with anatomical, electrophysiological, pharmacological, and molecular techniques to explore how the local expression of synapse-specific genes and proteins contributes to synapse elimination in the development and maturation of synaptic connections. Dr. Schacher and his colleagues will examine whether regulation of local protein s ynthesis in the presynaptic and/or postsynaptic cell and the expression and distribution of critical surface receptors contribute to synapse elimination at different stages in the life history of an identified and behaviorally relevant chemical synapse.
