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Inhibitory interneurons show early dysfunction in a SOD1 mouse model of ALS

C. F. Cavarsan, P. R. Steele, L. M. McCane, K. J. LaPre, A. C. Puritz, N. Katenka, View ORCID ProfileK. A. Quinlan
doi: https://doi.org/10.1101/2020.10.21.348359
C. F. Cavarsan
1George and Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, 02881 USA
2Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, 02881 USA
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P. R. Steele
1George and Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, 02881 USA
2Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, 02881 USA
3Interdisciplinary Neuroscience Program, University of Rhode Island, Kingston, RI, 02881 USA
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L. M. McCane
3Interdisciplinary Neuroscience Program, University of Rhode Island, Kingston, RI, 02881 USA
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K. J. LaPre
1George and Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, 02881 USA
2Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, 02881 USA
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A. C. Puritz
4Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611 USA
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N. Katenka
5Department of Computer Science and Statistics, University of Rhode Island, Kingston, RI, 02881 USA
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K. A. Quinlan
1George and Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, 02881 USA
2Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, 02881 USA
4Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611 USA
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  • ORCID record for K. A. Quinlan
  • For correspondence: kaquinlan@uri.edu
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Abstract

Few studies in amyotrophic lateral sclerosis (ALS) focus on the premotor interneurons synapsing onto motoneurons (MNs). We hypothesized inhibitory interneurons contribute to dysfunction, particularly if altered before MN neuropathology. We directly assessed excitability and morphology of ventral lumbar glycinergic interneurons from SOD1G93AGlyT2eGFP (SOD1) and wildtype GlyT2eGFP (WT) mice. SOD1 interneurons were smaller but density was unchanged. Patch clamp revealed dampened excitability in SOD1 interneurons, including depolarized PICs and voltage threshold. Renshaw cells (RCs; confirmed with immunohistochemistry) showed similar dampened excitability. Morphology and electrophysiology were used to create a “random forest” statistical model to predict RCs when histological verification was not possible. Predicted SOD1 RCs were less excitable (consistent with experimental results); predicted SOD1 non-RCs were more excitable. In summary, inhibitory interneurons show very early perturbations poised to impact MNs, modify motor output, and provide early biomarkers of ALS. Therapeutics like riluzole that universally reduce CNS excitability could exacerbate this dysfunction.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 21, 2020.
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Inhibitory interneurons show early dysfunction in a SOD1 mouse model of ALS
C. F. Cavarsan, P. R. Steele, L. M. McCane, K. J. LaPre, A. C. Puritz, N. Katenka, K. A. Quinlan
bioRxiv 2020.10.21.348359; doi: https://doi.org/10.1101/2020.10.21.348359
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Inhibitory interneurons show early dysfunction in a SOD1 mouse model of ALS
C. F. Cavarsan, P. R. Steele, L. M. McCane, K. J. LaPre, A. C. Puritz, N. Katenka, K. A. Quinlan
bioRxiv 2020.10.21.348359; doi: https://doi.org/10.1101/2020.10.21.348359

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