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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, J-P; Delpire, E; Rouleau, GA; Raoul, C; Scamps, F

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


Authors

C Salsac

V Bernard

C Soulard

A Dionne

E Coque

S Benlefki

P Hince

PA Dion

G Butler-Browne

W Camu

J-P Bouchard

E Delpire

GA Rouleau

C Raoul

F Scamps



Abstract

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 a1 in spinal cord motoneurons. Moreover, the activity-targeting drug carbamazepine restores Na(+)/K(+)-ATPase a1 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.

Journal Article Type Article
Acceptance Date Jun 20, 2017
Online Publication Date Jun 21, 2017
Publication Date 2017-10
Publicly Available Date Mar 29, 2024
Journal Neurobiology of Disease
Print ISSN 0969-9961
Electronic ISSN 0969-9961
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 106
Pages 35 - 48
DOI https://doi.org/10.1016/j.nbd.2017.06.013
Keywords Motoneuron; Andermann syndrome; Chloride homeostasis; Electrical activity; Neuromuscular junction; Na+/K+ ATPase
Publisher URL http://www.sciencedirect.com/science/article/pii/S0969996117301407?via%3Dihub