KCC3 loss-of-function contributes to Andermann syndrome by inducing activity-dependent neuromuscular junction defects.

Bowerman M, Salsac C, Bernard V, Soulard C, Dionne A, Coque E, Benlefki S, Hince P, Dion PA, Butler-Browne G, Camu W, Bouchard JP, Delpire E, Rouleau GA, Raoul C, Scamps F
Neurobiol Dis. 2017 106: 35-48

PMID: 28647557 · DOI:10.1016/j.nbd.2017.06.013

Loss-of-function mutations in the potassium-chloride cotransporter KCC3 lead to Andermann syndrome, a severe sensorimotor neuropathy characterized by areflexia, amyotrophy and locomotor abnormalities. The molecular events responsible for axonal loss remain poorly understood. Here, we establish that global or neuron-specific KCC3 loss-of-function in mice leads to early neuromuscular junction (NMJ) abnormalities and muscular atrophy that are consistent with the pre-synaptic neurotransmission defects observed in patients. KCC3 depletion does not modify chloride handling, but promotes an abnormal electrical activity among primary motoneurons and mislocalization of Na/K-ATPase α1 in spinal cord motoneurons. Moreover, the activity-targeting drug carbamazepine restores Na/K-ATPase α1 localization and reduces NMJ denervation in Slc12a6 mice. We here propose that abnormal motoneuron electrical activity contributes to the peripheral neuropathy observed in Andermann syndrome.

Copyright © 2017 Elsevier Inc. All rights reserved.

MeSH Terms (17)

Agenesis of Corpus Callosum Animals Carbamazepine Cells, Cultured Chlorides Disease Models, Animal Mice, Inbred C57BL Mice, Transgenic Motor Neurons Neuromuscular Junction Neurotransmitter Agents Peripheral Nervous System Diseases Presynaptic Terminals Sodium-Potassium-Exchanging ATPase Spinal Cord Symporters Synaptic Transmission

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