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

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.

Citation

Bowerman, M., Salsac, C., Bernard, V., Soulard, C., Dionne, A., Coque, E., …Scamps, F. (2017). KCC3 loss-of-function contributes to Andermann syndrome by inducing activity-dependent neuromuscular junction defects. Neurobiology of Disease, 106, 35 - 48. https://doi.org/10.1016/j.nbd.2017.06.013

• Journal Article Type: Article
• Acceptance Date: Jun 20, 2017
• Online Publication Date: Jun 21, 2017
• Publication Date: 2017-10
• Publicly Available Date: May 26, 2023
• 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