Bowerman, M and Salsac, C and Bernard, V and Soulard, C and Dionne, A and Coque, E and Benlefki, S and Hince, P and Dion, PA and Butler-Browne, G and Camu, W and Bouchard, J-P and Delpire, E and Rouleau, GA and Raoul, C and Scamps, F (2017) KCC3 loss-of-function contributes to Andermann syndrome by inducing activity-dependent neuromuscular junction defects. Neurobiology of Disease, 106. 35 - 48. ISSN 1095-953X

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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 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.

Item Type: Article
Uncontrolled Keywords: Motoneuron; Andermann syndrome; Chloride homeostasis; Electrical activity; Neuromuscular junction; Na+/K+ ATPase
Subjects: Q Science > Q Science (General)
R Medicine > R Medicine (General)
Divisions: Faculty of Medicine and Health Sciences > Institute for Science and Technology in Medicine
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Depositing User: Symplectic
Date Deposited: 03 Nov 2017 12:23
Last Modified: 03 Nov 2017 12:23
URI: http://eprints.keele.ac.uk/id/eprint/4174

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