DEVELOPMENTAL REGULATION OF SYNAPTIC MOLECULAR ARCHITECTURE

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A central challenge in neurobiology concerns the mechanisms that govern moment-to-moment communication in the nervous system, subserving functions such as coordination and movement, and the mechanisms that underly long-term functions, including learning and memory. The synapse, the communicative junction between neurons, is acknowledged to play a pivotal role in these distinctively neural processes. Remarkably, however, the factors that regulate synaptic molecular structure and the identity or function of the majority of the novel molecules present in the synapse remain to be determined. Increasing evidence suggests that the postsynaptic density (PSD) is central to synaptic function. Nonetheless, among the 40 polypeptides found in the PSD, few proteins have been characterized biochemically. Yet this information is essential for comprehension of the roles the PSD plays in synaptic communication and plasticity. By monitoring the major postsynaptic density protein (mPSDp), we have recently demonstrated that the afferent innervation regulates synaptic structure in the sympathetic superior cervical ganglion and hippocampus of the rat. We have also defined aspects of synaptic molecular development in periphery and brain. The results suggest that the mPSDp, an autophosphorylatable Ca2+/calmodulin-dependent protein kinase, is a functionally important, structural synaptic protein exhibiting plasticity in response to environmental stimulation. We have purified the mPSDp to homogeneity and now plan to characterize the novel synaptic protein at the molecular level. The mPSDp is one of a number of proteins that is enriched in the PSD. Similarly, other proteins that are enriched in the PSD are candidates for important roles in synaptic function. We propose to characterize the purified mPSDp in detail biochemically and functionally. Using the same approaches as for mPSDp, we seek to (1) isolate, (2) characterize, and (3) perform functional studies on the five additional proteins, including brain dystrophin and protein tyrosine kinases, that are enriched in the PSD. By characterizing the various novel PSD proteins we may gain insight into the molecular basis of synaptic function and information processing in the nervous system.