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Severe Convulsions and Dysmyelination in Both Jimpy and Cx32/47 −/− Mice may Associate Astrocytic L-Channel Function with Myelination and Oligodendrocytic Connexins with Internodal Kv Channels

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Abstract

The Jimpy mouse illustrates the importance of interactions between astrocytes and oligodendrocytes. It has a mutation in Plp coding for proteolipid protein and DM20. Its behavior is normal at birth but from the age of ~2 weeks it shows severe convulsions associated with oligodendrocyte/myelination deficits and early death. A normally occurring increase in oxygen consumption by highly elevated K+ concentrations is absent in Jimpy brain slices and cultured astrocytes, reflecting that Plp at early embryonic stages affects common precursors as also shown by the ability of conditioned medium from normal astrocytes to counteract histological abnormalities. This metabolic response is now known to reflect opening of L-channels for Ca2+. The resulting deficiency in Ca2+ entry has many consequences, including lack of K+-stimulated glycogenolysis and release of gliotransmitter ATP. Lack of purinergic stimulation compromises oligodendrocyte survival and myelination and affects connexins and K+ channels. Mice lacking the oligodendrocytic connexins Cx32 and 47 show similar neurological dysfunction as Jimpy. This possibly reflects that K+ released by intermodal axonal Kv channels is transported underneath a loosened myelin sheath instead of reaching the extracellular space via connexin-mediated transport to oligodendrocytes, followed by release and astrocytic Na+,K+-ATPase-driven uptake with subsequent Kir4.1-facilitated release and neuronal uptake.

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Acknowledgements

Dr. Andrea Rivera, University of Porthmouth, U.K. is thanked for helpful discussions.

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Authors and Affiliations

  1. University of Saskatchewan, Saskatoon, Canada

    Y. H. Gerald Chaban

  2. Henry M. Jackson Foundation, Bethesda, MD, 20817, USA

    Ye Chen

  3. Laboratory of Metabolic Brain Diseases, Institute of Metabolic Disease Research and Drug Development, China Medical University, Shenyang, People’s Republic of China

    Elna Hertz & Leif Hertz

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Chaban, Y.H.G., Chen, Y., Hertz, E. et al. Severe Convulsions and Dysmyelination in Both Jimpy and Cx32/47 −/− Mice may Associate Astrocytic L-Channel Function with Myelination and Oligodendrocytic Connexins with Internodal Kv Channels. Neurochem Res 42, 1747–1766 (2017). https://doi.org/10.1007/s11064-017-2194-z

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