title: Altered intracellular Ca2+ homeostasis in nerve terminals of severe spinal muscular atrophy mice.
abstract: 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.
authors.affiliation: Department of Medical Physiology and Biophysics, School of Medicine, University of Seville, 41009 Seville, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Ruiz
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Casañas
authors.forename: Laura
authors.initials: L
authors.lastname: Torres-Benito
authors.forename: Raquel
authors.initials: R
authors.lastname: Cano
authors.forename: Lucía
authors.initials: L
authors.lastname: Tabares
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism*; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D045604:Extracellular Fluid / Q000378:metabolism*; D006706:Homeostasis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000503:physiopathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D009469:Neuromuscular Junction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018377:Neurotransmitter Agents / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism* / Q000473:pathology; D011930:Reaction Time; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics
chemical_list: D018377:Neurotransmitter Agents; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D002118:Calcium