The long-term goal of this research is to understand the overall physiological, anatomical, and functional organization of the mammalian hippocampus and hippocampal formation. In this proposal the focus is on modeling the electrical and chemical signals that occur in single CA1 pyramidal neurons based on experimental data. These models are being developed in parallel with ongoing experimental research in the same laboratory. The purpose in developing these models is tho supplement and extend our understanding of biophysically complex neurons as computational elements and to aid our intuition in the design and interpretation of experiments.
The specific aims of the project are: (1) to characterize the passive electrical properties of CA1 pyramidal neurons using whole-cell clamp and convention intracellular impalement recordings, in conjunction with cellular three-dimensional reconstruction and computer modeling; (2) to develop a more complete and realistic computer simulation of processes occurring in dendritic spines at the biophysical level, including the effects of intracellular diffusion and buffering of ions; (3) to develop more realistic models of the excitability of CA1 pyramidal cells, based on existing voltage clamp, histochemical, morphological and current- source density data; and (4) to use these simulations to determine the critical parameters for associativity and specificity for long-term potentiation (LTP) and long-term depression (LTD) in hippocampal neurons. The proposed research will use modeling tools that have been recently developed for simulating detailed models of dendritic trees with hundreds of compartments. The CABLE simulator developed by Hines and Moore will be modified to include the diffusion, binding, uptake and release of calcium and other diffusible second messengers. Simulations of calcium entry into dendritic trees through voltage-sensitive calcium channels and NMDA receptors will be compared directly with measurements made using calcium-sensitive dyes and confocal microscopy in the same laboratory. An accurate model of electrical and chemical processing in hippocampal neurons would be of benefit for many other investigations of hippocampal function and dysfunction, including epileptogenesis and memory impairments brought about by selective anatomical lesions and physiological imbalances.
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