The major aim of this research is to understand the molecular mechanisms of how precise and orderly sets of synaptic connections in the adult mammalian central nervous system (CNS) are formed during development. Specifically, this proposal focuses on the role of neural activity in the prenatal development of connections in the mammalian visual system between retina and one of its central targets, the lateral geniculate nucleus (L:GN). When retinal ganglion cell axons initially grow into the LGN they are intermixed. The adult unmixed pattern emerges during a period in which axons from the two eyes segregate in a process known to be activity- dependent because it can be blocked by target application of tetrodotoxin (TTX). To identify genes encoding putative components of the cascade of molecular events underlying activity-dependent development of neuronal connectivity we propose to screen for candidate genes that satisfy two major criteria: regulation by neuronal activity and expression in retinal ganglion cells and/or LGN neurons during the formation of eye-specific layers. The results of these experiments should help break the impasse in moving from a systems to a molecular level of analysis of activity- dependent development of neuronal connectivity and thereby provide opportunities to design pharmacological treatments for developmental disorders of the CNS. Moreover, because it is thought that activity- dependent mechanisms are not only operational during development, but are also preserved at least in part during memory and learning in adulthood, these studies have broad significance beyond the developmental period.
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