P7-23 Multiple measures of axonal excitability in a mouse model of Kennedy disease

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Objective: To examine motor nerve properties in a mouse model of spinal and bulbar muscular atrophy (SBMA), also known as Kennedy disease (KD) (i) to characterize excitability changes during disease progression and (ii) to determine how well the model reproduces the axonal excitability changes observed in SBMA patients. Methods.SBMA and Wild Type (WT) littermate male mice were recorded, under isoflurane anesthesia, between 3 and 20 months by stimulating the tibial branch of the sciatic motor nerve and recording compound muscle action potentials (CMAPs) from plantar muscles. As in patient studies, the multiple excitability program recorded stimulus-response, strengthduration and current-threshold relationships, threshold electrotonus and recovery-cycle. Since SBMA is a slowly progressive motor neuron pathology, data were divided in two groups (1) under 12 months when the mice are preor early symptomatic, and (2) over 12 months. Mutant and WT mice were compared. Results: In younger SBMA mice, no significant changes in excitability properties were observed compared to WT. In contrast, by 12 months, SBMA mice exhibited greater changes in response to depolarizing (p < 0.01) and hyperpolarizing (p < 0.001) currents, providing a fanning out appearance on the threshold electrotonus waveforms. Older SBMA mice also displayed smaller current/threshold gradients on the current-threshold relationship (p < 0.001). Some of these abnormalities were similar to those reported in patients with SBMA, but the change in current-threshold relationship was in the opposite direction. Furthermore, an increase in strength-duration time-constant, which was related to fasciculation frequency in the patients, was not significant in the SBMA mice. Conclusion: Although the SBMA mouse reproduces the motoneuron degeneration characteristic of SBMA and some of the axonal membrane changes, it is not a good model to explore the development of axonal hyperexcitability. Acknowledgments: This project was supported by MNDA. The authors gratefully acknowledge Mr Jim Dick for his assistance throughout this project.