11. Studying human neurophysiology using the mouse tail!. Issue 4 (April 2018) - Howells, James
Abstract : Introduction: Non-invasive threshold-tracking techniques have been used in vivo to probe the biophysical basis of many neuromuscular conditions in human subjects. However, there are ethical and practical limitations to the study of human subjects, and mouse models provide an alternative and complementary path. Transgenic mouse models and the use of mice during drug development make them attractive targets for axonal excitability studies. Aims: The objective of this study was to develop a mouse model that would allow the valid comparison of the excitability of both motor and sensory axons in mice to that of humans. Methods: Axonal excitability studies were performed in mice by stimulating at the base of the tail using non-polarisable Ag/AgCl ring electrodes and recording CMAP and SNAP responses distally using platinum needle electrodes. The results were compared to human studies, and a mathematical model of the excitability of mouse axons was developed. Results: Forty-nine threshold-tracking studies were performed in mice aged 16–20 weeks with no adverse outcomes (30 M/19F). The excitability waveforms of mice were qualitatively similar to those recorded from human median nerve at the wrist. Mathematical modelling suggested that mouse and human axons are structurally similar, and that the differences are due to smaller Na +, larger fast K +, smaller slow K + and larger hyperpolarization-activated currents. Conclusions: Motor and sensory excitability studies are readily achievable in mature mice. The results and modelling suggest that, while there are quantitative differences in mouse and human axons, structurally the same channels and morphology underlie their excitability. As is the case in human studies on median nerve at the wrist, the mouse tail provides a valid model of axonal excitability, and this allows the assessment of motor and sensory function. This technique and the mathematical model should be useful for translational studies.