title: A Stem Cell Model of the Motor Circuit Uncouples Motor Neuron Death from Hyperexcitability Induced by SMN Deficiency.
abstract: In spinal muscular atrophy, a neurodegenerative disease caused by ubiquitous deficiency in the survival motor neuron (SMN) protein, sensory-motor synaptic dysfunction and increased excitability precede motor neuron (MN) loss. Whether central synaptic dysfunction and MN hyperexcitability are cell-autonomous events or they contribute to MN death is unknown. We addressed these issues using a stem-cell-based model of the motor circuit consisting of MNs and both excitatory and inhibitory interneurons (INs) in which SMN protein levels are selectively depleted. We show that SMN deficiency induces selective MN death through cell-autonomous mechanisms, while hyperexcitability is a non-cell-autonomous response of MNs to defects in pre-motor INs, leading to loss of glutamatergic synapses and reduced excitation. Findings from our in vitro model suggest that dysfunction and loss of MNs result from differential effects of SMN deficiency in distinct neurons of the motor circuit and that hyperexcitability does not trigger MN death.
authors.affiliation: Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Simon
authors.affiliation: Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Janas
authors.affiliation: Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Lotti
authors.affiliation: Department of Neuroscience, Columbia University, New York, NY 10032, USA.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Tapia
authors.affiliation: Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA. Electronic address: lp2284@cumc.columbia.edu.
authors.forename: Livio
authors.initials: L
authors.lastname: Pellizzoni
authors.affiliation: Center for Motor Neuron Biology and Disease, Columbia University, New York, NY 10032, USA; Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA; Department of Neurology, Columbia University, New York, NY 10032, USA. Electronic address: gzmentis@columbia.edu.
authors.forename: George Z
authors.initials: GZ
authors.lastname: Mentis
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology*; D004195:Disease Models, Animal; D007395:Interneurons / Q000378:metabolism / Q000473:pathology; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology*; D009134:Muscular Atrophy, Spinal / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology*; D055533:Survival of Motor Neuron 1 Protein / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism / Q000473:pathology
chemical_list: C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein