Derangements in synaptic transmission are an important part of the pathology of several neurological and mental diseases including epilepsy, schizophrenia, depression and perhaps Alzheimer's disease. Despite the medical significance of synaptic transmission and the important roles of synapses in information processing and storage in the brain, relatively little is known about the molecular mechanisms underlying regulation of synaptic transmission. The proposed research involves a study of the molecular structures of synapses in the central nervous system (CNS). It focuses on the identification and study of proteins associated with the postsynaptic density (PSD) a large fibrous specialization of the submembrane cytoskeleton that adheres to the postsynaptic membrane opposite presynaptic terminals. PSDs are especially prominent in glutamatergic terminals in the CNS where they are believed to function as anchoring sites for synaptic receptors and signal transduction molecules as well as for molecules mediating adhesion between the pre and postsynaptic membranes. The applicants have applied modern cell biological and microchemical methods to sequence and characterized several proteins associated with the PSD, including NR2B, a subunit of the NMDA receptors, PSD-95, an apparent clustering and adapter molecule, and densin-180, an apparent new adhesion molecule. Here they propose to extend their studies by completing the characterization of two additional PSD proteins that we have sequenced, by beginning to study the association among the PSD proteins that mediate assembly and function of the PSD, and by using recombinant DNA methodology to test hypothesis about the specific functions of PSD proteins in the synapse.
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