Most afferent projections to the cerebellar cortex are topographically organized and terminate in sagittally stripes. The studies proposed in this application will identify the intrinsic and extrinsic factors regulating the development of afferent topography, synapse stabilization and stripe formation in the cerebellar cortex. One series of experiments will determine if early developing, highly topographically organized olivocerebellar (IO-CB) projections establish a framework to guide later developing afferent pathways to appropriate areas of termination. The role of presynaptic impulse activity, the N-methyl-D-aspartate (NMDA) receptor and postsynaptic activity on afferent synapse stabilization and stripe formation will be examined separately. The effects of TTX blockade of impulse activity in developing IO-CB and spinocerebellar (Sp-CB) projection on synapse specification and the formation of stripes will be determined. The requirement for impulse activity for the stabilization of normally transient cerebrocerebellar (Cx-CB) projections will be examined following excitation of Cx-CB projection neurons. The role of cerebellar cortical neuronal activity on the development of stripes and synapse specification and stabilization will be evaluated. Chronic inhibition of cortical neurons will be used to determine if IO-CB and Sp-CB pathways form stripe patterns of termination and if appropriate connections are established. In other experiments chronic excitation of cerebellar cortical neurons will be used to determine if postsynaptic activation is sufficient for stabilizing functionally silent Cx-CB synapses. IN a final series of experiments the role of the NMDA receptor in the development of afferent stripes will be evaluated following chronic exposure to NMDA antagonists and agonists. Our hypothesis predict that IO-CB projections serve to guide all other afferents to appropriate areas of the cortex and that presynaptic impulse activity, the NMDA receptor and postsynaptic activity are conjointly required for cerebellar afferent synapse stabilization and the formation of stripes.
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