KCC3 loss-of-function contributes to Andermann syndrome by inducing activity-dependent neuromuscular junction defects.
Neurobiol Dis
; 106: 35-48, 2017 Oct.
Article
en En
| MEDLINE
| ID: mdl-28647557
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.
Palabras clave
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Terminales Presinápticos
/
Transmisión Sináptica
/
Enfermedades del Sistema Nervioso Periférico
/
Simportadores
/
Agenesia del Cuerpo Calloso
/
Neuronas Motoras
/
Unión Neuromuscular
Límite:
Animals
Idioma:
En
Revista:
Neurobiol Dis
Asunto de la revista:
NEUROLOGIA
Año:
2017
Tipo del documento:
Article
País de afiliación:
Reino Unido