Biomedical Application Projects

    Biophysical factors underlying the variability of synaptic signals. 
    This project includes collaborators in the Computational Neurobiology Laboratory at the Salk Institute and the National Center for Microscopy and Imaging Research at the University of California San Diego. Synaptic microphysiology determines the variability of signal size and time course, and synaptic variability in turn influences the reliability and amount of information that can be encoded in neuronal signals. Many biophysical factors contribute to signal variability, including the amount of neurotransmitter in synaptic vesicles, the kinetics of neurotransmitter release, regional differences in synaptic cleft volume, and the distributions and kinetics of neurotransmitter receptors, reuptake proteins, enzymes, and other participating molecules. The relative importance of these different factors is largely unknown and can be investigated using MCell simulations of synaptic signals in spatially realistic models.  To do the simulations it is necessary to reconstruct or otherwise build representative synaptic ultrastructure using DReAMM and other software, and then to simulate signals while systematically varying spatial and kinetic parameters. In the clinical setting, derangement of synaptic structure and/or function contributes directly or indirectly to the etiology of many diseases, including neurodegenerative movement disorders (e.g., Parkinson's), dementias (e.g., Alzheimer's), affective disorders (e.g., bipolar or major depression), and neuromuscular diseases (e.g., Myasthenia Gravis, Lambert Eaton Syndrome, Slow Channel or AChE deficiency myasthenic syndromes).

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