Altered intracellular Ca2+ homeostasis in nerve terminals of severe spinal muscular atrophy mice

J Neurosci. 2010 Jan 20;30(3):849-57. doi: 10.1523/JNEUROSCI.4496-09.2010.


Low levels of survival motor neuron (SMN) protein result in spinal muscular atrophy (SMA), a severe genetic disease characterized by motor impairment and premature lethality. Although SMN is a ubiquitous protein, motor neurons are much more vulnerable to low levels of SMN than other cells. To gain insight into the pathogenesis of SMA, we have compared synaptic function of motor terminals in wild-type and severe SMA mice at different ages and in two proximal muscles. Our results show that mutant muscle fibers fire normal action potentials and that multi-innervated terminals are functional. By studying the characteristics of the three main components of synaptic transmission in nerve terminals (spontaneous, evoked, and asynchronous release), we found that the kinetics of the postsynaptic potentials are slowed and evoked neurotransmitter release is decreased by approximately 55%. In addition, asynchronous release is increased approximately 300%, indicating an anomalous augmentation of intraterminal bulk Ca(2+) during repetitive stimulation. Together, these results show that the reduction of SMN affects synaptic maturation, evoked release, and regulation of intraterminal Ca(2+) levels.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology
  • Animals
  • Animals, Newborn
  • Calcium / metabolism*
  • Disease Models, Animal
  • Electric Stimulation / methods
  • Extracellular Fluid / metabolism*
  • Homeostasis* / genetics
  • Mice
  • Mice, Transgenic
  • Models, Biological
  • Muscle, Skeletal / physiopathology
  • Muscular Atrophy, Spinal / genetics
  • Muscular Atrophy, Spinal / pathology*
  • Mutation / genetics
  • Neuromuscular Junction / metabolism
  • Neuromuscular Junction / pathology
  • Neuromuscular Junction / physiopathology
  • Neurotransmitter Agents / metabolism
  • Presynaptic Terminals / metabolism*
  • Presynaptic Terminals / pathology
  • Reaction Time
  • Survival of Motor Neuron 1 Protein / genetics


  • Neurotransmitter Agents
  • Smn1 protein, mouse
  • Survival of Motor Neuron 1 Protein
  • Calcium