Abstract
While the mouse presents an invaluable experimental model organism in biology, its usefulness in cardiac arrhythmia research is limited in some aspects due to major electrophysiological differences between murine and human action potentials (APs). As previously described, these species-specific traits can be partly overcome by application of a cell-type transforming clamp (CTC) to anthropomorphize the murine cardiac AP. CTC is a hybrid experimental-computational dynamic clamp technique, in which a computationally calculated time-dependent current is inserted into a cell in real-time, to compensate for the differences between sarcolemmal currents of that cell (e.g., murine) and the desired species (e.g., human). For effective CTC performance, mismatch between the measured cell and a mathematical model used to mimic the measured AP must be minimal. We have developed a genetic algorithm (GA) approach that rapidly tunes a mathematical model to reproduce the AP of the murine cardiac myocyte under study. Compared to a prior implementation that used a template-based model selection approach, we show that GA optimization to a cell-specific model results in a much better recapitulation of the desired AP morphology with CTC. This improvement was more pronounced when anthropomorphizing neonatal mouse cardiomyocytes to human-like APs than to guinea pig APs. CTC may be useful for a wide range of applications, from screening effects of pharmaceutical compounds on ion channel activity, to exploring variations in the mouse or human genome. Rapid GA optimization of a cell-specific mathematical model improves CTC performance and may therefore expand the applicability and usage of the CTC technique.
Highlights
Dynamic clamp is a closed-loop hybrid experimentalcomputational technique that permits probing a living cell with current-clamp perturbations that are calculated functions of instantaneous measurements of the behavior of the cell
Genomic resources for the mouse (Genome Reference Consortium, 2012) are rapidly increasing, and celltype transforming clamp (CTC) can be added as a new tool to screen for phenotypes in excitable cell dynamics, e.g., arising from mutations or polymorphisms in genes encoding for ion channels or for ion channel regulatory proteins
action potentials (APs) transformations across species can help overcome the inherent difficulties in translating murine electrophysiological and pathophysiological traits into relevant human counter properties
Summary
Dynamic clamp is a closed-loop hybrid experimentalcomputational technique that permits probing a living cell with current-clamp perturbations that are calculated functions of instantaneous measurements of the behavior of the cell. Dynamic clamp is useful for investigating ion channel function and ionic current dynamics (Dorval et al, 2001; Prinz et al, 2004; Raikov et al, 2004; Bettencourt et al, 2008). One particular research topic that may benefit from dynamic clamp tools is the study of interspecies differences in action potentials (AP) of excitable cells, such as cardiac myocytes. Such interspecies differences can limit the extent to which results from animal models can be extrapolated to human physiology. Given the importance of the mouse as a model organism, novel insights into interspecies differences and techniques to overcome them are valuable
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