1. Neuronal activity disrupts myelinated axon integrity in the absence of NKCC1b.
- Author
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Marshall-Phelps KLH, Kegel L, Baraban M, Ruhwedel T, Almeida RG, Rubio-Brotons M, Klingseisen A, Benito-Kwiecinski SK, Early JJ, Bin JM, Suminaite D, Livesey MR, Möbius W, Poole RJ, and Lyons DA
- Subjects
- Action Potentials, Amino Acid Sequence, Animals, Animals, Genetically Modified, Axons drug effects, Axons ultrastructure, Central Nervous System drug effects, Central Nervous System metabolism, Central Nervous System pathology, Embryo, Nonmammalian, Gene Expression Regulation, Developmental, Humans, Mutation, Myelin Sheath drug effects, Myelin Sheath ultrastructure, Neurons drug effects, Neurons ultrastructure, Peripheral Nervous System drug effects, Peripheral Nervous System metabolism, Peripheral Nervous System pathology, Schwann Cells drug effects, Schwann Cells ultrastructure, Sequence Alignment, Sequence Homology, Amino Acid, Signal Transduction, Sodium Channel Blockers toxicity, Solute Carrier Family 12, Member 2 deficiency, Tetrodotoxin toxicity, Zebrafish, Zebrafish Proteins deficiency, Axons metabolism, Myelin Sheath metabolism, Neurons metabolism, Schwann Cells metabolism, Solute Carrier Family 12, Member 2 genetics, Zebrafish Proteins genetics
- Abstract
Through a genetic screen in zebrafish, we identified a mutant with disruption to myelin in both the CNS and PNS caused by a mutation in a previously uncharacterized gene, slc12a2b, predicted to encode a Na+, K+, and Cl- (NKCC) cotransporter, NKCC1b. slc12a2b/NKCC1b mutants exhibited a severe and progressive pathology in the PNS, characterized by dysmyelination and swelling of the periaxonal space at the axon-myelin interface. Cell-type-specific loss of slc12a2b/NKCC1b in either neurons or myelinating Schwann cells recapitulated these pathologies. Given that NKCC1 is critical for ion homeostasis, we asked whether the disruption to myelinated axons in slc12a2b/NKCC1b mutants is affected by neuronal activity. Strikingly, we found that blocking neuronal activity completely prevented and could even rescue the pathology in slc12a2b/NKCC1b mutants. Together, our data indicate that NKCC1b is required to maintain neuronal activity-related solute homeostasis at the axon-myelin interface, and the integrity of myelinated axons., (© 2020 Marshall-Phelps et al.)
- Published
- 2020
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