William R. Holmes, Ph.D.

     The goal of my research is to develop mathematical and computational models of individual neurons of the hippocampus that will be appropriate for use in network models.  The immediate focus is to develop highly detailed models of dentate granule cells that describe appropriately how computation and synaptic modification occur in these cells.  These highly detailed models must satisfy the constraints imposed by experimental data including conditions leading to long-term potentiation (LTP) and long-term depression (LTD).

     Modeling work is proceeding on molecular, synaptic and neuron levels. On the molecular level, a model of a dendritic spine is being extended to include calcium binding to calmodulin and calmodulin binding and trapping by CaM-kinase II with the hope of being able to express the essence of these biochemical reactions in a synaptic modification rule. On the synaptic level, diffusion models of the synaptic cleft have been developed to determine more accurate descriptions of NMDA and AMPA conductances for use in neuron level models. On the neuron level, detailed morphology is being used in simulations to determine the range of computational possibilities of neurons as constrained by the spatial and temporal distribution of synaptic and non-synaptic conductances. Methods are being developed to determine appropriate parameter values for the conductances.

Selected References:

• Li, Y. and Holmes, W.R. 2000. Comparison of CaMKinase II activation in a dendritic spine computed with deterministic and stochastic models of the NMDA synaptic conductance. Neurocomputing 32-33:1-7.

• Holmes, W.R. 2000. Models of calmodulin trapping and CaM Kinase II activation in a dendritic spine. J. Comput. Neurosci. 8:65-85.

• Aradi, I. and Holmes, W.R. 1999. Active dendrites regulate spatio-temporal integration in hippocampal dentate granule cells. Neurocomputing 26-27:45-51.

• Aradi, I. and Holmes, W.R. 1999. Role of multiple calcium and calcium-dependent conductances in regulation of hippocampal dentate granule cell excitability. J. Comput. Neurosci. 6:215-235.

• Holmes, W.R. and Aradi, I. 1998. Modeling the contributions of calcium channels and NMDA receptor channels to calcium current in dendritic spines. In: Computional Neuroscience: Trends in Research, 1998. J.M. Bower, editor. pp. 191-196.

• Holmes, W.R. and Levy, W.B. 1997. Quantifying the role of inhibition in associative long-term potentiation in dentate granule cells with computational models. J. Neurophysiol. 78:103-116.