The long-term goal of this research is to understand the function of the hippocampus. The hippocampus is thought to play an important role in learning and memory functions and is involved in a number of major neurological disorders. If we are to understand hippocampal function, we must understand how computation and synaptic modification take place in the cells of the hippocampus. Computer modeling is a new and powerful tool for studying hippocampal function. Computer models of individual neurons can he used to test hypotheses difficult to address experimentally and can provide specific predictions about the mechanisms of observed phenomena. In this research highly detailed models of hippocampal dentate granule cells will be developed. These models will include complete morphology along with mathematical descriptions of synaptic and non-synaptic conductances and of processes that control calcium concentration in the cell. Models will be made as realistic as possible to be consistent with the considerable body of experimental data available. These highly detailed models will be used to: 1) Assess the importance of the morphological and electrotonic structure for the function of dentate granule cells. 2) Determine the range of computational possibilities of these cells given their complement of ion channel types, distributions and densities. How the computational possibilities change when certain parameter values change might reveal phenomena seen with certain pathological conditions. 3) Explain how calcium concentration changes in the cell might be correlated with the induction of long-term potentiation (LTP) or long-term depression (LTD). If we understand how LTP and LTD occur, we will have made great strides towards understanding how learning and memory take place. 4) Deduce a means to include synaptic modification in models that is consistent with experimental observations of LTP and LTD. This research will provide a quantitative understanding of computation and synaptic modification in dentate granule cells. This will tell us how highly detailed models might be reduced to simple descriptions of dentate granule cells that retain the essential computational features of these cells. These simple descriptions can then be used in complex network models to investigate hippocampal function.
