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

• DOI: 10.1016/j.nbd.2017.06.013
• Publication Date: 2017-06-22T06:00:14Z
• Authors: Melissa Bowerman; Céline Salsac; Véronique Bernard; Claire Soulard; Annie Dionne; Emmanuelle Coque; Salim Benlefki; Pascale Hince; Patrick A. Dion; Gillian Butler-Br...; William Camu; Jean-Pierre Bouchard; Eric Delpire; Guy A. Rouleau; Cédric Raoul; Frédérique Scamps
• Keywords: Amyotrophy; Loss function; Neuromuscular transmission

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.