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

Neurobiol Dis. 2017 Oct;106:35-48. doi: 10.1016/j.nbd.2017.06.013. Epub 2017 Jun 21.


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.

Keywords: Andermann syndrome; Chloride homeostasis; Electrical activity; Motoneuron; Na(+)/K(+) ATPase; Neuromuscular junction.

MeSH terms

  • Agenesis of Corpus Callosum / drug therapy
  • Agenesis of Corpus Callosum / metabolism*
  • Agenesis of Corpus Callosum / pathology
  • Animals
  • Carbamazepine / pharmacology
  • Cells, Cultured
  • Chlorides / metabolism
  • Disease Models, Animal
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Neurons / drug effects
  • Motor Neurons / metabolism*
  • Motor Neurons / pathology
  • Neuromuscular Junction / drug effects
  • Neuromuscular Junction / metabolism*
  • Neuromuscular Junction / pathology
  • Neurotransmitter Agents / pharmacology
  • Peripheral Nervous System Diseases / drug therapy
  • Peripheral Nervous System Diseases / metabolism*
  • Peripheral Nervous System Diseases / pathology
  • Presynaptic Terminals / drug effects
  • Presynaptic Terminals / metabolism*
  • Presynaptic Terminals / pathology
  • Sodium-Potassium-Exchanging ATPase / metabolism
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism
  • Spinal Cord / pathology
  • Symporters / deficiency*
  • Symporters / genetics
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / physiology*


  • Chlorides
  • Neurotransmitter Agents
  • Slc12a6 protein, mouse
  • Symporters
  • Carbamazepine
  • Sodium-Potassium-Exchanging ATPase

Supplementary concepts

  • Corpus callosum agenesis neuronopathy