Reduced sensory synaptic excitation impairs motor neuron function via Kv2.1 in spinal muscular atrophy

Nat Neurosci. 2017 Jul;20(7):905-916. doi: 10.1038/nn.4561. Epub 2017 May 15.


Behavioral deficits in neurodegenerative diseases are often attributed to the selective dysfunction of vulnerable neurons via cell-autonomous mechanisms. Although vulnerable neurons are embedded in neuronal circuits, the contributions of their synaptic partners to disease process are largely unknown. Here we show that, in a mouse model of spinal muscular atrophy (SMA), a reduction in proprioceptive synaptic drive leads to motor neuron dysfunction and motor behavior impairments. In SMA mice or after the blockade of proprioceptive synaptic transmission, we observed a decrease in the motor neuron firing that could be explained by the reduction in the expression of the potassium channel Kv2.1 at the surface of motor neurons. Chronically increasing neuronal activity pharmacologically in vivo led to a normalization of Kv2.1 expression and an improvement in motor function. Our results demonstrate a key role of excitatory synaptic drive in shaping the function of motor neurons during development and the contribution of its disruption to a neurodegenerative disease.

MeSH terms

  • Action Potentials / physiology
  • Animals
  • Cell Survival / physiology
  • Disease Models, Animal
  • Kainic Acid / pharmacology
  • Metalloendopeptidases / pharmacology
  • Mice
  • Mice, Transgenic
  • Motor Neurons / drug effects
  • Motor Neurons / metabolism
  • Motor Neurons / physiology*
  • Muscular Atrophy, Spinal / physiopathology*
  • Neuromuscular Junction / physiology
  • Proprioception / physiology*
  • Reflex, Righting / physiology
  • Shab Potassium Channels / biosynthesis
  • Shab Potassium Channels / physiology*
  • Survival of Motor Neuron 1 Protein / genetics
  • Survival of Motor Neuron 2 Protein / genetics
  • Synapses / drug effects
  • Synapses / physiology*
  • Tetanus Toxin / pharmacology


  • SMN2 protein, human
  • Shab Potassium Channels
  • Smn1 protein, mouse
  • Survival of Motor Neuron 1 Protein
  • Survival of Motor Neuron 2 Protein
  • Tetanus Toxin
  • Metalloendopeptidases
  • zinc-endopeptidase, tetanus neurotoxin
  • Kainic Acid