TY - JOUR
T1 - Hyperexcitability precedes motoneuron loss in the Smn2B/ - mouse model of spinal muscular atrophy
AU - Quinlan, Katharina A
AU - Reedich, E. J.
AU - Arnold, W. D.
AU - Puritz, A. C.
AU - Cavarsan, C. F.
AU - Heckman, C. J.
AU - DiDonato, Christine J
N1 - Funding Information:
This study was made possible through funding from National Institute of Neurological Disorders and Stroke (NINDS) Grants R01NS060926 and 3R01NS060926-07S1 (to C. J. DiDonato) and with additional support from Muscular Dystrophy Association Grant MDA418685 (to C. J. DiDonato). K. A. Quinlan received additional support from a springboard fellowship from Target ALS. During this work, E. J. Reedich was the Dr. Virginia Mullin Investigator and was supported in part by NINDS Training Grant T32NS041234 and by the Stanley Manne Children’s Research Institute and the Ann & Robert H. Lurie Children’s Hospital of Chicago. Experiments were performed in the laboratories of C. J. DiDonato, C. J. Heckman, and K. A. Quinlan.
Publisher Copyright:
Copyright © 2019 the American Physiological Society
PY - 2019
Y1 - 2019
N2 - Spinal motoneuron dysfunction and loss are pathological hallmarks of the neuromuscular disease spinal muscular atrophy (SMA). Changes in motoneuron physiological function precede cell death, but how these alterations vary with disease severity and motoneuron maturational state is unknown. To address this question, we assessed the electrophysiology and morphology of spinal motoneurons of presymptomatic Smn2B/ - mice older than 1 wk of age and tracked the timing of motor unit loss in this model using motor unit number estimation (MUNE). In contrast to other commonly used SMA mouse models, Smn2B/ - mice exhibit more typical postnatal development until postnatal day (P)11 or 12 and have longer survival (~3 wk of age). We demonstrate that Smn2B/ - motoneuron hyperexcitability, marked by hyperpolarization of the threshold voltage for action potential firing, was present at P9–10 and preceded the loss of motor units. Using MUNE studies, we determined that motor unit loss in this mouse model occurred 2 wk after birth. Smn2B/ - motoneurons were also larger in size, which may reflect compensatory changes taking place during postnatal development. This work suggests that motoneuron hyperexcitability, marked by a reduced threshold for action potential firing, is a pathological change preceding motoneuron loss that is common to multiple models of severe SMA with different motoneuron maturational states. Our results indicate voltage-gated sodium channel activity may be altered in the disease process. NEW & NOTEWORTHY Changes in spinal motoneuron physiologic function precede cell death in spinal muscular atrophy (SMA), but how they vary with maturational state and disease severity remains unknown. This study characterized motoneuron and neuromuscular electrophysiology from the Smn2B/ - model of SMA. Motoneurons were hyperexcitable at postnatal day (P)9–10, and specific electrophysiological changes in Smn2B/ - motoneurons preceded functional motor unit loss at P14, as determined by motor unit number estimation studies.
AB - Spinal motoneuron dysfunction and loss are pathological hallmarks of the neuromuscular disease spinal muscular atrophy (SMA). Changes in motoneuron physiological function precede cell death, but how these alterations vary with disease severity and motoneuron maturational state is unknown. To address this question, we assessed the electrophysiology and morphology of spinal motoneurons of presymptomatic Smn2B/ - mice older than 1 wk of age and tracked the timing of motor unit loss in this model using motor unit number estimation (MUNE). In contrast to other commonly used SMA mouse models, Smn2B/ - mice exhibit more typical postnatal development until postnatal day (P)11 or 12 and have longer survival (~3 wk of age). We demonstrate that Smn2B/ - motoneuron hyperexcitability, marked by hyperpolarization of the threshold voltage for action potential firing, was present at P9–10 and preceded the loss of motor units. Using MUNE studies, we determined that motor unit loss in this mouse model occurred 2 wk after birth. Smn2B/ - motoneurons were also larger in size, which may reflect compensatory changes taking place during postnatal development. This work suggests that motoneuron hyperexcitability, marked by a reduced threshold for action potential firing, is a pathological change preceding motoneuron loss that is common to multiple models of severe SMA with different motoneuron maturational states. Our results indicate voltage-gated sodium channel activity may be altered in the disease process. NEW & NOTEWORTHY Changes in spinal motoneuron physiologic function precede cell death in spinal muscular atrophy (SMA), but how they vary with maturational state and disease severity remains unknown. This study characterized motoneuron and neuromuscular electrophysiology from the Smn2B/ - model of SMA. Motoneurons were hyperexcitable at postnatal day (P)9–10, and specific electrophysiological changes in Smn2B/ - motoneurons preceded functional motor unit loss at P14, as determined by motor unit number estimation studies.
KW - Electrophysiology
KW - Motoneuron
KW - Mouse
KW - SMN
KW - Spinal muscular atrophy
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UR - http://www.scopus.com/inward/citedby.url?scp=85073184471&partnerID=8YFLogxK
U2 - 10.1152/jn.00652.2018
DO - 10.1152/jn.00652.2018
M3 - Article
C2 - 31365319
AN - SCOPUS:85073184471
VL - 122
SP - 1297
EP - 1311
JO - Journal of Neurophysiology
JF - Journal of Neurophysiology
SN - 0022-3077
IS - 4
ER -