Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the loss of motor neurons leading to progressive paralysis and death. Using transcranial magnetic stimulation (TMS) and nerve excitability tests, several clinical studies have identified that cortical and peripheral hyperexcitability are among the earliest pathologies observed in ALS patients. The changes in the electrophysiological properties of motor neurons have been identified in both sporadic and familial ALS patients, despite the diverse etiology of the disease. The mechanisms behind the change in neuronal signalling are not well understood, though current findings implicate intrinsic changes in motor neurons and dysfunction of cells critical in regulating motor neuronal excitability, such as astrocytes and interneurons. Alterations in ion channel expression and/or function in motor neurons has been associated with changes in cortical and peripheral nerve excitability. In addition to these intrinsic changes in motor neurons, inhibitory signalling through GABAergic interneurons is also impaired in ALS, likely contributing to increased neuronal excitability. Astrocytes have also recently been implicated in increasing neuronal excitability in ALS by failing to adequately regulate glutamate levels and extracellular K+ concentration at the synaptic cleft. As hyperexcitability is a common and early feature of ALS, it offers a therapeutic and diagnostic target. Thus, understanding the underlying pathways and mechanisms leading to hyperexcitability in ALS offers crucial insight for future development of ALS treatments.
Similar content being viewed by others
References
Cleveland DW, Rothstein JD (2001) From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nat Rev Neurosci 2:806–819. doi:10.1038/35097565
Kiernan JA, Hudson AJ (1991) Changes in sizes of cortical and lower motor neurons in amyotrophic lateral sclerosis. Brain 114(Pt 2):843–853
Logroscino G, Traynor BJ, Hardiman O, Chiò A, Mitchell D, Swingler RJ, Millul A, Benn E et al (2010) Incidence of amyotrophic lateral sclerosis in Europe. J Neurol Neurosurg Psychiatry 81:385–390. doi:10.1136/jnnp.2009.183525
Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, Burrell JR, Zoing MC (2011) Amyotrophic lateral sclerosis. Lancet 377:942–955. doi:10.1016/S0140-6736(10)61156-7
Bensimon G, Lacomblez L, Meininger V (1994) A controlled trial of riluzole in amyotrophic lateral sclerosis. N Engl J Med 330:585–591. doi:10.1056/NEJM199403033300901
Miller RG, Mitchell JD, Moore DH (2012) Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database of Systematic Reviews
Brooks BR, Miller RG, Swash M, Munsat TL, World Federation of Neurology Research Group on Motor Neuron Diseases (2000) El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 1:293–299
Chiò A (1999) ISIS survey: an international study on the diagnostic process and its implications in amyotrophic lateral sclerosis. J Neurol 246(Suppl 3):III1–III5
Bowser R, Turner MR, Shefner J (2011) Biomarkers in amyotrophic lateral sclerosis: opportunities and limitations. Nat Rev Neurol 7:631–638. doi:10.1038/nrneurol.2011.151
Chen S, Sayana P, Zhang X, Le W (2013) Genetics of amyotrophic lateral sclerosis: an update. Mol Neurodegener 8:28. doi:10.1186/1750-1326-8-28
Ling S-C, Polymenidou M, Cleveland DW (2013) Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron 79:416–438. doi:10.1016/j.neuron.2013.07.033
Renton AE, Chiò A, Traynor BJ (2014) State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci 17:17–23. doi:10.1038/nn.3584
Robberecht W, Philips T (2013) The changing scene of amyotrophic lateral sclerosis. Nat Rev Neurosci 14:248–264. doi:10.1038/nrn3430
Bae JS, Simon NG, Menon P, Vucic S, Kiernan MC (2013) The puzzling case of hyperexcitability in amyotrophic lateral sclerosis. J Clin Neurol 9:65–74. doi:10.3988/jcn.2013.9.2.65
Vucic S, Nicholson GA, Kiernan MC (2008) Cortical hyperexcitability may precede the onset of familial amyotrophic lateral sclerosis. Brain 131:1540–1550. doi:10.1093/brain/awn071
Blair IP, Williams KL, Warraich ST, Durnall JC, Thoeng AD, Manavis J, Blumbergs PC, Vucic S et al (2010) FUS mutations in amyotrophic lateral sclerosis: clinical, pathological, neurophysiological and genetic analysis. J Neurol Neurosurg Psychiatry 81:639–645. doi:10.1136/jnnp.2009.194399
Williams KL, Fifita JA, Vucic S, Durnall JC, Kiernan MC, Blair IP, Nicholson GA (2013) Pathophysiological insights into ALS with C9ORF72 expansions. J Neurol Neurosurg Psychiatry 84:931–935. doi:10.1136/jnnp-2012-304529
Mills KR, Nithi KA (1997) Corticomotor threshold is reduced in early sporadic amyotrophic lateral sclerosis. Muscle Nerve 20:1137–1141. doi:10.1002/(SICI)1097-4598(199709)20:9<1137::AID-MUS7>3.0.CO;2-9
de Carvalho M, Swash M (2013) Fasciculation potentials and earliest changes in motor unit physiology in ALS. J Neurol Neurosurg Psychiatry 84:963–968. doi:10.1136/jnnp-2012-304545
de Carvalho M, Dengler R, Eisen A, England JD, Kaji R, Kimura J, Mills K, Mitsumoto H et al (2008) Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol 119:497–503. doi:10.1016/j.clinph.2007.09.143
Vucic S, Kiernan MC (2006) Novel threshold tracking techniques suggest that cortical hyperexcitability is an early feature of motor neuron disease. Brain 129:2436–2446. doi:10.1093/brain/awl172
Menon P, Kiernan MC, Vucic S (2015) Cortical hyperexcitability precedes lower motor neuron dysfunction in ALS. Clin Neurophysiol 126:803–809. doi:10.1016/j.clinph.2014.04.023
Weber M, Eisen A, Stewart H, Hirota N (2000) The split hand in ALS has a cortical basis. J Neurol Sci 180:66–70. doi:10.1016/S0022-510X(00)00430-5
Kujirai T, Caramia MD, Rothwell JC, Day BL, Thompson PD, Ferbert A, Wroe S, Asselman P et al (1993) Corticocortical inhibition in human motor cortex. J Physiol Lond 471:501–519
McClintock SM, Freitas C, Oberman L, Lisanby SH, Pascual-Leone A (2011) Transcranial magnetic stimulation: a neuroscientific probe of cortical function in schizophrenia. Biol Psychiatry 70:19–27. doi:10.1016/j.biopsych.2011.02.031
Ziemann U, Winter M, Reimers CD, Reimers K, Tergau F, Paulus W (1997) Impaired motor cortex inhibition in patients with amyotrophic lateral sclerosis evidence from paired transcranial magnetic stimulation. Neurology 49:1292–1298. doi:10.1212/WNL.49.5.1292
Vucic S, Kiernan MC (2006) Axonal excitability properties in amyotrophic lateral sclerosis. Clin Neurophysiol 117:1458–1466. doi:10.1016/j.clinph.2006.04.016
Bostock H, Rothwell JC (1997) Latent addition in motor and sensory fibres of human peripheral nerve. J Physiol 498:277–294
Bostock H, Cikurel K, Burke D (1998) Threshold tracking techniques in the study of human peripheral nerve. Muscle Nerve 21:137–158. doi:10.1002/(SICI)1097-4598(199802)21:2<137::AID-MUS1>3.0.CO;2-C
Bostock H, Sharief MK, Reid G, Murray NMF (1995) Axonal ion channel dysfunction in amyotrophic lateral sclerosis. Brain 118:217–225. doi:10.1093/brain/118.1.217
Pieri M, Carunchio I, Curcio L, Mercuri NB, Zona C (2009) Increased persistent sodium current determines cortical hyperexcitability in a genetic model of amyotrophic lateral sclerosis. Exp Neurol 215:368–379. doi:10.1016/j.expneurol.2008.11.002
Mogyoros I, Kiernan MC, Burke D, Bostock H (1998) Strength-duration properties of sensory and motor axons in amyotrophic lateral sclerosis. Brain 121:851–859. doi:10.1093/brain/121.5.851
Kanai K, Kuwabara S, Misawa S, Tamura N, Ogawara K, Nakata M, Sawai S, Hattori T et al (2006) Altered axonal excitability properties in amyotrophic lateral sclerosis: impaired potassium channel function related to disease stage. Brain 129:953–962. doi:10.1093/brain/awl024
Wagle-Shukla A, Ni Z, Gunraj CA, Bahl N, Chen R (2009) Effects of short interval intracortical inhibition and intracortical facilitation on short interval intracortical facilitation in human primary motor cortex. J Physiol 587:5665–5678. doi:10.1113/jphysiol.2009.181446
Moser JM, Bigini P, Schmitt-John T (2013) The wobbler mouse, an ALS animal model. Mol Gen Genomics 288:207–229. doi:10.1007/s00438-013-0741-0
McGown A, McDearmid JR, Panagiotaki N, Tong H, Al Mashhadi S, Redhead N, Lyon AN, Beattie CE et al (2013) Early interneuron dysfunction in ALS: insights from a mutant sod1 zebrafish model. Ann Neurol 73:246–258. doi:10.1002/ana.23780
Zhang W, Zhang L, Liang B, Schroeder D, Zhang Z, Cox GA, Li Y, Lin D-T (2016) Hyperactive somatostatin interneurons contribute to excitotoxicity in neurodegenerative disorders. Nat Neurosci 19:557–559. doi:10.1038/nn.4257
Nieto-Gonzalez JL, Moser J, Lauritzen M, Schmitt-John T, Jensen K (2011) Reduced GABAergic inhibition explains cortical hyperexcitability in the wobbler mouse model of ALS. Cereb Cortex 21:625–635. doi:10.1093/cercor/bhq134
Nihei K, McKee AC, Kowall NW (1993) Patterns of neuronal degeneration in the motor cortex of amyotrophic lateral sclerosis patients. Acta Neuropathol 86:55–64
Petri S, Krampfl K, Hashemi F, Grothe C, Hori A, Dengler R, Bufler J (2003) Distribution of GABAA receptor mRNA in the motor cortex of ALS patients. J Neuropathol Exp Neurol 62:1041–1051. doi:10.1093/jnen/62.10.1041
Lloyd CM, Richardson MP, Brooks DJ, Al-Chalabi A, Leigh PN (2000) Extramotor involvement in ALS: PET studies with the GABAA ligand [11C]flumazenil. Brain 123:2289–2296. doi:10.1093/brain/123.11.2289
Vucic S, Kiernan MC (2010) Upregulation of persistent sodium conductances in familial ALS. J Neurol Neurosurg Psychiatry 81:222–227. doi:10.1136/jnnp.2009.183079
Kuo JJ, Siddique T, Fu R, Heckman CJ (2005) Increased persistent Na+ current and its effect on excitability in motoneurones cultured from mutant SOD1 mice. J Physiol 563:843–854. doi:10.1113/jphysiol.2004.074138
Geevasinga N, Menon P, Ng K, Bos MVD, Byth K, Kiernan MC, Vucic S (2016) Riluzole exerts transient modulating effects on cortical and axonal hyperexcitability in ALS. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 0:1–9. doi:10.1080/21678421.2016.1188961
Vucic S, Lin CS-Y, Cheah BC, Murray J, Menon P, Krishnan AV, Kiernan MC (2013) Riluzole exerts central and peripheral modulating effects in amyotrophic lateral sclerosis. Brain 136:1361–1370. doi:10.1093/brain/awt085
Jiang Y-M, Yamamoto M, Kobayashi Y, Yoshihara T, Liang Y, Terao S, Takeuchi H, Ishigaki S et al (2005) Gene expression profile of spinal motor neurons in sporadic amyotrophic lateral sclerosis. Ann Neurol 57:236–251. doi:10.1002/ana.20379
Shibuya K, Misawa S, Arai K, Nakata M, Kanai K, Yoshiyama Y, Ito K, Isose S et al (2011) Markedly reduced axonal potassium channel expression in human sporadic amyotrophic lateral sclerosis: an immunohistochemical study. Exp Neurol 232:149–153. doi:10.1016/j.expneurol.2011.08.015
Van Den Bosch L, Van Damme P, Bogaert E, Robberecht W (2006) The role of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis. Biochim Biophys Acta (BBA) - Mol Basis Dis 1762:1068–1082. doi:10.1016/j.bbadis.2006.05.002
Rothstein J (1994) Excitotoxic mechanisms in the pathogenesis of amyotrophic lateral sclerosis. Adv Neurol 68:7–20–7
Doble A (1996) The pharmacology and mechanism of action of riluzole. Neurology 47:S233–S241
Rothstein JD, Tsai G, Kuncl RW, Clawson L, Cornblath DR, Drachman DB, Pestronk A, Stauch BL et al (1990) Abnormal excitatory amino acid metabolism in amyotrophic lateral sclerosis. Ann Neurol 28:18–25. doi:10.1002/ana.410280106
Rothstein JD, Van Kammen M, Levey AI, Martin LJ, Kuncl RW (1995) Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 38:73–84
Pardo AC, Wong V, Benson LM, Dykes M, Tanaka K, Rothstein JD, Maragakis NJ (2006) Loss of the astrocyte glutamate transporter GLT1 modifies disease in SOD1G93A mice. Exp Neurol 201:120–130. doi:10.1016/j.expneurol.2006.03.028
Lin C-LG, Bristol LA, Jin L, Dykes-Hoberg M, Crawford T, Clawson L, Rothstein JD (1998) Aberrant RNA processing in a neurodegenerative disease: the cause for absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis. Neuron 20:589–602. doi:10.1016/S0896-6273(00)80997-6
Nagai M, Abe K, Okamoto K, Itoyama Y (1998) Identification of alternative splicing forms of GLT-1 mRNA in the spinal cord of amyotrophic lateral sclerosis patients. Neurosci Lett 244:165–168. doi:10.1016/S0304-3940(98)00158-X
Kofuji P, Newman E (2004) Potassium buffering in the central nervous system. Neuroscience 129:1045–1056
Haj-Yasein NN, Jensen V, Vindedal GF, Gundersen GA, Klungland A, Ottersen OP, Hvalby O, Nagelhus EA (2011) Evidence that compromised K+ spatial buffering contributes to the epileptogenic effect of mutations in the human Kir4.1 gene (KCNJ10). Glia 59:1635–1642. doi:10.1002/glia.21205
Djukic B, Casper KB, Philpot BD, Chin L-S, McCarthy KD (2007) Conditional knock-out of Kir4.1 leads to glial membrane depolarization, inhibition of potassium and glutamate uptake, and enhanced short-term synaptic potentiation. J Neurosci 27:11354–11365. doi:10.1523/JNEUROSCI.0723-07.2007
Bataveljić D, Nikolić L, Milosević M, Todorović N, Andjus PR (2012) Changes in the astrocytic aquaporin-4 and inwardly rectifying potassium channel expression in the brain of the amyotrophic lateral sclerosis SOD1G93A rat model. Glia 60:1991–2003. doi:10.1002/glia.22414
Kaiser M, Maletzki I, Hülsmann S, Holtmann B, Schulz-Schaeffer W, Kirchhoff F, Bähr M, Neusch C (2006) Progressive loss of a glial potassium channel (KCNJ10) in the spinal cord of the SOD1 (G93A) transgenic mouse model of amyotrophic lateral sclerosis. J Neurochem 99:900–912. doi:10.1111/j.1471-4159.2006.04131.x
Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S (2007) Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci 10:615–622. doi:10.1038/nn1876
Haidet-Phillips AM, Hester ME, Miranda CJ, Meyer K, Braun L, Frakes A, Song S, Likhite S et al (2011) Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nat Biotechnol 29:824–828. doi:10.1038/nbt.1957
Philips T, Robberecht W (2011) Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease. The Lancet Neurology 10:253–263. doi:10.1016/S1474-4422(11)70015-1
Das MM, Svendsen CN (2015) Astrocytes show reduced support of motor neurons with aging that is accelerated in a rodent model of ALS. Neurobiol Aging 36:1130–1139. doi:10.1016/j.neurobiolaging.2014.09.020
Almad AA, Doreswamy A, Gross SK, Richard J-P, Huo Y, Haughey N, Maragakis NJ (2016) Connexin 43 in astrocytes contributes to motor neuron toxicity in amyotrophic lateral sclerosis. Glia 64:1154–1169. doi:10.1002/glia.22989
Leroy F, Zytnicki D (2015) Is hyperexcitability really guilty in amyotrophic lateral sclerosis? Neural Regen Res 10:1413–1415. doi:10.4103/1673-5374.165308
Leroy F, d’Incamps BL, Imhoff-Manuel RD, Zytnicki D (2014) Early intrinsic hyperexcitability does not contribute to motoneuron degeneration in amyotrophic lateral sclerosis. eLife 3:e04046. doi:10.7554/eLife.04046
Delestrée N, Manuel M, Iglesias C, Elbasiouny SM, Heckman CJ, Zytnicki D (2014) Adult spinal motoneurones are not hyperexcitable in a mouse model of inherited amyotrophic lateral sclerosis. J Physiol 592:1687–1703. doi:10.1113/jphysiol.2013.265843
Shibuya K, Misawa S, Kimura H, Noto Y-I, Sato Y, Sekiguchi Y, Iwai Y, Mitsuma S et al (2015) A single blind randomized controlled clinical trial of mexiletine in amyotrophic lateral sclerosis: efficacy and safety of sodium channel blocker phase II trial. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 16:353–358. doi:10.3109/21678421.2015.1038277
Weiss MD, Macklin EA, Simmons Z et al (2016) A randomized trial of mexiletine in ALS safety and effects on muscle cramps and progression. Neurology 86:1474–1481. doi:10.1212/WNL.0000000000002507
Wainger BJ, Kiskinis E, Mellin C, Wiskow O, Han SSW, Sandoe J, Perez NP, Williams LA et al (2014) Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep 7:1–11. doi:10.1016/j.celrep.2014.03.019
Engel M, Do-Ha D, Muñoz SS, Ooi L (2016) Common pitfalls of stem cell differentiation: a guide to improving protocols for neurodegenerative disease models and research. Cell Mol Life Sci 73:3693–3709. doi:10.1007/s00018-016-2265-3
Devlin A-C, Burr K, Borooah S, Foster JD, Cleary EM, Geti I, Vallier L, Shaw CE et al (2015) Human iPSC-derived motoneurons harbouring TARDBP or C9ORF72 ALS mutations are dysfunctional despite maintaining viability. Nat Commun 6:5999. doi:10.1038/ncomms6999
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Do-Ha, D., Buskila, Y. & Ooi, L. Impairments in Motor Neurons, Interneurons and Astrocytes Contribute to Hyperexcitability in ALS: Underlying Mechanisms and Paths to Therapy. Mol Neurobiol 55, 1410–1418 (2018). https://doi.org/10.1007/s12035-017-0392-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12035-017-0392-y