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

Neurobiology of Disease

William Camu¹  Frédérique Scamps¹  Véronique Bernard¹  Eric Delpire²  Salim Benlefki³  Pascale Hince⁴  Claire Soulard⁵  Gillian Butler-Browne⁶  Céline Salsac⁶  Cédric Raoul⁶  Guy A. Rouleau⁷  Melissa Bowerman⁷  Patrick A. Dion⁷  Annie Dionne⁷  Jean-Pierre Bouchard⁸  Emmanuelle Coque⁹ 

[1] 2, Montpellier, France;CHU de Québec, Hôpital de l'Enfant-Jésus, Département des sciences neurologiques, Québec, Québec, Canada;CNRS UMR8246, Paris, France;Inserm U1130, Paris, France;University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford, UK;;Université Montpellier 1 &The Institute for Neurosciences of Montpellier, Inserm UMR1051, Saint Eloi Hospital, Montpellier, France;Université Laval, Québec, Canada;Université Pierre et Marie Curie UM CR 18, Paris, France;

关键词: Motoneuron;    Andermann syndrome;    Chloride homeostasis;    Electrical activity;    Neuromuscular junction;    Na+/K+ ATPase;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown