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Functional Recovery of Regenerating Motor Axons is Delayed in Mice Heterozygously Deficient for the Myelin Protein P0 Gene

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Abstract

Mice with a heterozygous knock-out of the myelin protein P0 gene (P0+/−) develop a neuropathy similar to human Charcot–Marie–Tooth disease. They are indistinguishable from wild-types (WT) at birth and develop a slowly progressing demyelinating neuropathy. The aim of this study was to investigate whether the regeneration capacity of early symptomatic P0+/− is impaired as compared to age matched WT. Right sciatic nerves were lesioned at the thigh in 7–8 months old mice. Tibial motor axons at ankle were investigated by conventional motor conduction studies and axon excitability studies using threshold tracking. To evaluate regeneration we monitored the recovery of motor function after crush, and then compared the fiber distribution by histology. The overall motor performance was investigated using Rotor-Rod. P0+/− had reduced compound motor action potential amplitudes and thinner myelinated axons with only a borderline impairment in conduction and Rotor-Rod. Plantar muscle reinnervation occurred within 21 days in all mice. Shortly after reinnervation the conduction of P0+/− regenerated axons was markedly slower than WT, however, this difference decayed with time. Nevertheless, after 1 month, regenerated P0+/− axons had longer strength-duration time constant, larger threshold changes during hyperpolarizing electrotonus and longer relative refractory period. Their performance at Rotor-Rod remained also markedly impaired. In contrast, the number and diameter distribution of regenerating myelinated fibers became similar to regenerated WT. Our data suggest that in the presence of heterozygously P0 deficient Schwann cells, regenerating motor axons retain their ability to reinnervate their targets and remyelinate, though their functional recovery is delayed.

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Acknowledgments

The project was supported by Lundbeck Foundation, the Novo Nordisk Foundation, the Danish Medical Research Council, the Ludvig and Sara Elsass Foundation, the Foundation for Research in Neurology and Jytte and Kaj Dahlboms Foundation. We would like to thank Lis Hansen for expert technical assistance with histological preparations.

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Authors and Affiliations

  1. Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3b, 2200, Copenhagen N, Denmark

    Mette Romer Rosberg, Susana Alvarez, Christian Krarup & Mihai Moldovan

  2. Department of Clinical Neurophysiology, Rigshospitalet, Copenhagen, Denmark

    Mette Romer Rosberg, Susana Alvarez, Christian Krarup & Mihai Moldovan

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  1. Mette Romer Rosberg
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  2. Susana Alvarez
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  3. Christian Krarup
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  4. Mihai Moldovan
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Correspondence to Mihai Moldovan.

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Special Issue: In Honor of Elisabeth Bock.

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Rosberg, M.R., Alvarez, S., Krarup, C. et al. Functional Recovery of Regenerating Motor Axons is Delayed in Mice Heterozygously Deficient for the Myelin Protein P0 Gene. Neurochem Res 38, 1266–1277 (2013). https://doi.org/10.1007/s11064-013-1030-3

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  • DOI: https://doi.org/10.1007/s11064-013-1030-3

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