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

Melissa Bowerman; Céline Salsac; Véronique Bernard; Claire Soulard; Annie Dionne; Emmanuelle Coque; Salim Benlefki; Pascale Hince; Patrick A Dion; Gillian Butler-Browne; William Camu; Jean-Pierre Bouchard; Eric Delpire; Guy A Rouleau; Cédric Raoul; Frédérique Scamps

doi:10.1016/j.nbd.2017.06.013

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.

Authors

Melissa Bowerman¹, Céline Salsac², Véronique Bernard³, Claire Soulard⁴, Annie Dionne⁵, Emmanuelle Coque⁴, Salim Benlefki⁴, Pascale Hince⁶, Patrick A Dion⁶, Gillian Butler-Browne⁷, William Camu⁸, Jean-Pierre Bouchard⁵, Eric Delpire⁹, Guy A Rouleau¹⁰, Cédric Raoul⁴, Frédérique Scamps¹¹

Affiliations

¹ The Institute for Neurosciences of Montpellier, Inserm UMR1051, Saint Eloi Hospital, Montpellier, France; Université Montpellier 1 & 2, Montpellier, France; University of Oxford, Department of Physiology, Anatomy and Genetics, Oxford, UK.
² The Institute for Neurosciences of Montpellier, Inserm UMR1051, Saint Eloi Hospital, Montpellier, France.
³ Université Pierre et Marie Curie UM CR 18, Paris, France; CNRS UMR8246, Paris, France; Inserm U1130, Paris, France.
⁴ The Institute for Neurosciences of Montpellier, Inserm UMR1051, Saint Eloi Hospital, Montpellier, France; Université Montpellier 1 & 2, Montpellier, France.
⁵ Université Laval, Québec, Canada; CHU de Québec, Hôpital de l'Enfant-Jésus, Département des sciences neurologiques, Québec, Québec, Canada.
⁶ Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada; Department of Pathology and Cellular Biology, Université de Montréal, Montréal, Québec, Canada.
⁷ UM76, Institut de Myologie, Université Pierre et Marie Curie, Paris, France; U974, Inserm, Paris, France; UMR7215, CNRS, GH Pitié Salpêtrière, Paris, France.
⁸ The Institute for Neurosciences of Montpellier, Inserm UMR1051, Saint Eloi Hospital, Montpellier, France; Department of Neurology, ALS Reference Center, Gui-de-Chauliac Hospital, Montpellier, France.
⁹ Vanderbilt University Medical Center, Vanderbilt, USA.
¹⁰ Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada.
¹¹ The Institute for Neurosciences of Montpellier, Inserm UMR1051, Saint Eloi Hospital, Montpellier, France; Université Montpellier 1 & 2, Montpellier, France. Electronic address: [email protected].

PMID: 28647557
DOI: 10.1016/j.nbd.2017.06.013

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.

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*

Substances

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

Supplementary concepts

Corpus callosum agenesis neuronopathy

Grants and funding

R01 GM074771/GM/NIGMS NIH HHS/United States