The research in this proposal is designed to test the hypothesis that the long-lasting character of stimulus train-induced bursting (STIB), a model for epilepsy, is protein synthesis dependent and correlated with morphologic changes. By appropriate tetanic stimulation of input and recurrent pathways, both CA1 and CA3 subfields of hippocampus may be induced to fire spontaneous, epileptiform bursts of field potentials; this can be produced in vitro in the hippocampal slice and the change in excitability generally lasts for the life of the slice (about 10 hours). The baseline characteristics of this hyperexcitability in both subfields will be examined electrophysiologically both extra- and intracellularly, and these results will be correlated with differences in dendritic spine number and shape between control and bursting slices. Further, the parameters for and results of STIB will be compared to those of long-term potentiation (LTP), a model for learning that depends on stimulus tetany to produce response potentiation; the two models differ only slightly in their stimulus parameters, yet this results in functionally critical differences in excitability. Once this fundamental information is collected, further studies will test the hypotheses that: protein synthesis is necessary for the long-term maintenance of STIB in CA1 and CA3; STID and LTP have a parallel course of development temporally, and the difference between the development of LTP and STIB in hippocampal pyramidal neurons is a threshold effect; the intracellular responses of hippocampal pyramidal neurons during the development and maintenance of LTP and STIB differ quantitatively rather than qualitatively; the development and maintenance of STIB in the hippocampus produces changes in the shape and possibly the number of dendritic spines in the stimulated subfields, the specific examination beginning with the apical dendrites of pyramidal neurons in CAl; some of the changes in dendritic spine morphology are protein synthesis-dependent; and, some of the proteins synthesized in association with STIB subserve the plasticity of both LTP and STIB. In each case, regardless of whether the hypothesis is correct or not, the outcome will yield valuable information on cellular processes that are relevant to epilepsy, learning and memory, or both.
