Elucidation of the biochemical mechanisms involved in the storage of information in the nervous system is a fundamental problem in neurobiology. Studies of the processes underlying the phenomenon of long-term potentiation (LTP) of synaptic transmission at excitatory synapses elicited by brief bursts of high frequency stimulation have identified several components postulated to play a critical role in the way some patterns of electrical activity can alter the efficacy of synaptic transmission. In particular, the properties of one subclass of receptors for the acidic amino acid, L-glutamate, appear to be responsible for the induction of LTP in some telencephalic pathways, while the long-term changes in synaptic efficacy might depend on the activation of a calcium-dependent protease (calpain) and the partial proteolysis of a cytoskeletal protein, fodrin or brain spectrin. We have developed new techniques to study both the recognition site and the functional properties of different classes of glutamate receptors and have identified a number of regulatory mechanisms that could underlie various types of physiological plasticity. More specifically, we can now study the properties of the recognition sites for at least 3 classes of glutamate receptors using binding techniques and various radio- labeled 3H-ligands. The functional properties of the same receptors in the same membrane fractions can also be studied following their reconstitution in artificial lipid bilayers. The specific goals of the present proposal are to i) determine the functional characteristics of adult glutamate receptors reconstituted in artifical lipid bilayers; ii) determine the regulatory mechanisms involved in glutamate receptor function using biochemical and biophysical techniques; iii) study the possibility that local dendritic synthesis of specific proteins is involved in the maintenance of LTP; and iv) test the involvement of specific biochemical mechanisms in LTP and learning and memory. It is our hope that these studies will provide a more detailed description of the biochemical events occurring during learning as well as new pharmacological tools to specifically manipulate these processes. ***//
