title: Spinal muscular atrophy patient-derived motor neurons exhibit hyperexcitability.
abstract: Spinal muscular atrophy (SMA) presents severe muscle weakness with limited motor neuron (MN) loss at an early stage, suggesting potential functional alterations in MNs that contribute to SMA symptom presentation. Using SMA induced pluripotent stem cells (iPSCs), we found that SMA MNs displayed hyperexcitability with increased membrane input resistance, hyperpolarized threshold, and larger action potential amplitude, which was mimicked by knocking down full length survival motor neuron (SMN) in non-SMA MNs. We further discovered that SMA MNs exhibit enhanced sodium channel activities with increased current amplitude and facilitated recovery, which was corrected by restoration of SMN1 in SMA MNs. Together we propose that SMN reduction results in MN hyperexcitability and impaired neurotransmission, the latter of which exacerbate each other via a feedback loop, thus contributing to severe symptoms at an early stage of SMA.
authors.affiliation: Waisman center, University of Wisconsin, Madison, WI, 53705, USA.
authors.forename: Huisheng
authors.initials: H
authors.lastname: Liu
authors.affiliation: Waisman center, University of Wisconsin, Madison, WI, 53705, USA.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Lu
authors.affiliation: Waisman center, University of Wisconsin, Madison, WI, 53705, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.affiliation: Waisman center, University of Wisconsin, Madison, WI, 53705, USA.
authors.forename: Zhongwei
authors.initials: Z
authors.lastname: Du
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06030, USA.
authors.forename: Xue-Jun
authors.initials: XJ
authors.lastname: Li
authors.affiliation: 1] Waisman center, University of Wisconsin, Madison, WI, 53705, USA [2] Department of Neuroscience and Department of Neurology, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53705, USA.
authors.forename: Su-Chun
authors.initials: SC
authors.lastname: Zhang
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D008564:Membrane Potentials; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism*; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics; D015222:Sodium Channels / Q000378:metabolism; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism; D055366:Synaptic Potentials
chemical_list: D012333:RNA, Messenger; D015222:Sodium Channels; D055533:Survival of Motor Neuron 1 Protein