{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:52:25Z","timestamp":1785433945893,"version":"3.56.0"},"posted":{"date-parts":[[2026,3,25]]},"group-title":"Neuroscience","reference-count":45,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T00:00:00Z","timestamp":1774396800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["NS110953"],"award-info":[{"award-number":["NS110953"]}],"id":[{"id":"https:\/\/ror.org\/01s5ya894","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/04ty4v362","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,3,25]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Riluzole is the most commonly prescribed among the limited approved therapies for amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by progressive motoneuron loss and paralysis. It is thought to act by suppressing motoneuron excitability and glutamate release, but its clinical benefits are modest and often diminish over time. We previously showed that homeostatic mechanisms in the SOD1\n                  <jats:sup>G93A<\/jats:sup>\n                  (mSOD1) mouse model of ALS are hyperactive and prone to overcompensation. Here, we tested whether such dysregulated homeostasis antagonizes the effects of riluzole. Wild-type (WT) and presymptomatic mSOD1 mice received therapeutic doses of riluzole in drinking water for 10 days, with untreated littermates of both genotypes serving as controls. Motoneuron excitability and synaptic inputs were then examined using intracellular recordings from the isolated sacral spinal cord. The data showed that chronic riluzole treatment increased motoneuron excitability and polysynaptic inputs in mSOD1 mice but produced no detectable changes in WT motoneurons. These results suggest that hyperactive homeostatic mechanisms in ALS counteract the suppressive effects of riluzole. Notably, mSOD1 motoneurons exhibited larger membrane capacitance than WT, consistent with their increased cell size at this disease stage. Riluzole treatment reduced motoneuron membrane capacitance in mSOD1 mice to the range observed in WT animals, indicating normalization of cell size and potentially reduction in metabolic demand. Together, these findings help explain the limited clinical efficacy of riluzole while revealing a previously unrecognized neuroprotective mechanism of the drug in ALS.\n                <\/jats:p>","DOI":"10.64898\/2026.03.23.713695","type":"posted-content","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T04:25:59Z","timestamp":1774499159000},"source":"Crossref","is-referenced-by-count":2,"title":["Riluzole treatment paradoxically increases motoneuron excitability in ALS due to hyperactive homeostasis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9027-1960","authenticated-orcid":false,"given":"Amr A.","family":"Mahrous","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA, 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4821-5225","authenticated-orcid":false,"given":"Bradley S.","family":"Heit","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA, 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1324-7278","authenticated-orcid":false,"given":"CJ","family":"Heckman","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA, 60611"},{"name":"Department of Physical Therapy and Human Movement Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA, 60611"},{"name":"Department of Physical Medicine and Rehabilitation, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA, 60611"},{"name":"Shirley Ryan AbilityLab, Chicago, IL, USA, 60611"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026032910434263000_2026.03.23.713695v1.1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.50.1.62"},{"key":"2026032910434263000_2026.03.23.713695v1.2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410390203"},{"key":"2026032910434263000_2026.03.23.713695v1.3","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD001447.pub3"},{"key":"2026032910434263000_2026.03.23.713695v1.4","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2008.06211.x"},{"key":"2026032910434263000_2026.03.23.713695v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/S0028-3908(98)00081-1"},{"key":"2026032910434263000_2026.03.23.713695v1.6","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2006.107094"},{"key":"2026032910434263000_2026.03.23.713695v1.7","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.2000.00242.x"},{"key":"2026032910434263000_2026.03.23.713695v1.8","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0703424"},{"key":"2026032910434263000_2026.03.23.713695v1.9","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00587.2012"},{"key":"2026032910434263000_2026.03.23.713695v1.10","doi-asserted-by":"publisher","DOI":"10.1111\/j.1755-5949.2009.00116.x"},{"key":"2026032910434263000_2026.03.23.713695v1.11","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199403033300901"},{"key":"2026032910434263000_2026.03.23.713695v1.12","unstructured":"Mitchell, C.S. and R.H. Lee , Dynamic Meta-Analysis as a Therapeutic Prediction Tool for Amyotrophic Lateral Sclerosis, in Amyotrophic Lateral Sclerosis, M.H. Maurer , Editor. 2012, InTech."},{"key":"2026032910434263000_2026.03.23.713695v1.13","doi-asserted-by":"publisher","DOI":"10.3389\/FNCEL.2015.00248"},{"key":"2026032910434263000_2026.03.23.713695v1.14","doi-asserted-by":"crossref","unstructured":"Huh, S. , C.J. Heckman , and M. Manuel , Time Course of Alterations in Adult Spinal Motoneuron Properties in the SOD1(G93A) Mouse Model of ALS. eNeuro, 2021. 8(2).","DOI":"10.1523\/ENEURO.0378-20.2021"},{"key":"2026032910434263000_2026.03.23.713695v1.15","doi-asserted-by":"publisher","DOI":"10.1113\/JP275498"},{"key":"2026032910434263000_2026.03.23.713695v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-65685-8"},{"issue":"7-8","key":"2026032910434263000_2026.03.23.713695v1.17","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1080\/21678421.2016.1188961","article-title":"Riluzole exerts transient modulating effects on cortical and axonal hyperexcitability in ALS","volume":"17","year":"2016","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener"},{"key":"2026032910434263000_2026.03.23.713695v1.18","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00929.2016"},{"key":"2026032910434263000_2026.03.23.713695v1.19","doi-asserted-by":"crossref","unstructured":"Mahrous, A. , et al., Muscle Spasms after Spinal Cord Injury Stem from Changes in Motoneuron Excitability and Synaptic Inhibition, Not Synaptic Excitation. J Neurosci, 2024. 44(1).","DOI":"10.1523\/JNEUROSCI.1695-23.2023"},{"key":"2026032910434263000_2026.03.23.713695v1.20","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2019.00359"},{"key":"2026032910434263000_2026.03.23.713695v1.21","doi-asserted-by":"crossref","unstructured":"Manuel, M. , Suboptimal Discontinuous Current-Clamp Switching Rates Lead to Deceptive Mouse Neuronal Firing. eNeuro, 2021. 8(1).","DOI":"10.1523\/ENEURO.0461-20.2020"},{"key":"2026032910434263000_2026.03.23.713695v1.22","doi-asserted-by":"publisher","DOI":"10.1152\/jn.01068.2006"},{"key":"2026032910434263000_2026.03.23.713695v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(69)86467-2"},{"key":"2026032910434263000_2026.03.23.713695v1.24","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1984.sp015473"},{"key":"2026032910434263000_2026.03.23.713695v1.25","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3260-09.2009"},{"key":"2026032910434263000_2026.03.23.713695v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2017.08.041"},{"key":"2026032910434263000_2026.03.23.713695v1.27","doi-asserted-by":"publisher","DOI":"10.1152\/jn.1998.80.2.583"},{"key":"2026032910434263000_2026.03.23.713695v1.28","doi-asserted-by":"publisher","DOI":"10.1002\/mus.20261"},{"key":"2026032910434263000_2026.03.23.713695v1.29","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00788.2003"},{"key":"2026032910434263000_2026.03.23.713695v1.30","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.jpba.2017.08.045","article-title":"UPLC-MS\/MS assay of riluzole in human plasma and cerebrospinal fluid (CSF): Application in samples from spinal cord injured patients","volume":"146","year":"2017","journal-title":"J Pharm Biomed Anal"},{"key":"2026032910434263000_2026.03.23.713695v1.31","doi-asserted-by":"crossref","unstructured":"Shoenfeld, L. , et al., Soma size and Cav1.3 channel expression in vulnerable and resistant motoneuron populations of the SOD1G93A mouse model of ALS. Physiol Rep, 2014. 2(8).","DOI":"10.14814\/phy2.12113"},{"key":"2026032910434263000_2026.03.23.713695v1.32","doi-asserted-by":"publisher","DOI":"10.1007\/BF00370302"},{"issue":"2","key":"2026032910434263000_2026.03.23.713695v1.33","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/S0022-3565(24)36856-9","article-title":"Differential action of riluzole on tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels","volume":"282","year":"1997","journal-title":"J Pharmacol Exp Ther"},{"key":"2026032910434263000_2026.03.23.713695v1.34","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.47.6_Suppl_4.233S"},{"key":"2026032910434263000_2026.03.23.713695v1.35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0018681"},{"issue":"5-6","key":"2026032910434263000_2026.03.23.713695v1.36","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1080\/21678421.2017.1407796","article-title":"Riluzole does not improve lifespan or motor function in three ALS mouse models","volume":"19","year":"2018","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener"},{"key":"2026032910434263000_2026.03.23.713695v1.37","doi-asserted-by":"publisher","DOI":"10.1080\/17482960701856300"},{"key":"2026032910434263000_2026.03.23.713695v1.38","doi-asserted-by":"publisher","DOI":"10.1002\/cne.21818"},{"key":"2026032910434263000_2026.03.23.713695v1.39","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00665.2003"},{"key":"2026032910434263000_2026.03.23.713695v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2013.02.011"},{"key":"2026032910434263000_2026.03.23.713695v1.41","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2010.200659"},{"key":"2026032910434263000_2026.03.23.713695v1.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2007.07.003"},{"key":"2026032910434263000_2026.03.23.713695v1.43","doi-asserted-by":"publisher","DOI":"10.1038\/nn1653"},{"key":"2026032910434263000_2026.03.23.713695v1.44","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00714.2011"},{"key":"2026032910434263000_2026.03.23.713695v1.45","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1988.sp017336"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.03.23.713695","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,29]],"date-time":"2026-03-29T17:43:50Z","timestamp":1774806230000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.03.23.713695"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,25]]},"references-count":45,"URL":"https:\/\/doi.org\/10.64898\/2026.03.23.713695","relation":{},"subject":[],"published":{"date-parts":[[2026,3,25]]},"subtype":"preprint"}}