Different mechanisms contribute to motor cortex hyperexcitability in amyotrophic lateral sclerosis

Zanette, Giampietro; Tamburin, Stefano; Manganotti, Paolo; Refatti, Nicola; Forgione, Antonio; Rizzuto, N.

doi:10.1016/s1388-2457(02)00288-2

Cited by 142 publications

(116 citation statements)

References 44 publications

Supporting

Mentioning

103

Contrasting

Unclassified

Order By: Relevance

“…Overall, the enhanced motoneuron excitability provides an alternative viewpoint for the mechanism of selective motoneuron degeneration and reveals a possible link to previously published observations during the development of ALS (Zanette et al 2002). …”

Section: Discussionsupporting

confidence: 75%

“…In a recent study of particular importance (Zanette et al 2002), an increased gain of the dose-response curves to transcranial magnetic stimulation in ALS patients was reported. This increased gain is thought to result from an elevated excitability of the corticomotoneurons, therefore contributing to motor cortex hyperexcitability (Zanette et al 2002).…”

Section: Discussionmentioning

confidence: 94%

See 1 more Smart Citation

Hyperexcitability of Cultured Spinal Motoneurons From Presymptomatic ALS Mice

Kuo

Schonewille

Siddique

et al. 2004

Journal of Neurophysiology

169

151

View full text Add to dashboard Cite

of cultured spinal motoneurons from presymptomatic ALS mice. J Neurophysiol 91: 571-575, 2004. First published October 1, 2003 10.1152/jn.00665.2003. ALS (amyotrophic lateral sclerosis) is an adult-onset and deadly neurodegenerative disease characterized by a progressive and selective loss of motoneurons. Transgenic mice overexpressing a mutated human gene (G93A) coding for the enzyme SOD1 (Cu/Zn superoxide dismutase) develop a motoneuron disease resembling ALS in humans. In this generally accepted ALS model, we tested the electrophysiological properties of individual embryonic and neonatal spinal motoneurons in culture by measuring a wide range of electrical properties influencing motoneuron excitability during current clamp. There were no differences in the motoneuron resting potential, input conductance, action potential shape, or afterhyperpolarization between G93A and control motoneurons. The relationship between the motoneuron's firing frequency and injected current (f-I relation) was altered. The slope of the f-I relation and the maximal firing rate of the G93A motoneurons were much greater than in the control motoneurons. Differences in spontaneous synaptic input were excluded as a cause of increased excitability. This finding identifies a markedly elevated intrinsic electrical excitability in cultured embryonic and neonatal mutant G93A spinal motoneurons. We conclude that the observed intrinsic motoneuron hyperexcitability is induced by the SOD1 toxic gain-of-function through an aberration in the process of action potential generation. This hyperexcitability may play a crucial role in the pathogenesis of ALS as the motoneurons were cultured from presymptomatic mice.

show abstract

Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 94%

Hyperexcitability of Cultured Spinal Motoneurons From Presymptomatic ALS Mice

Kuo

Schonewille

Siddique

et al. 2004

Journal of Neurophysiology

169

151

View full text Add to dashboard Cite

show abstract

“…In living patients with ALS, electrophysiological data revealed impaired intracortical inhibition. 75,76 Positron emission tomography (PET) studies showed that binding of the benzodiazepine GABA(A) ligand flumazenil was reduced in the motor cortex of ALS patients. 77,78 In situ hybridization histochemistry studies also indicated that GABA(A)-receptor mRNA expression was reduced in postmortem cortical samples of ALS patients, 79,80 but unchanged in spinal cord of G93A-SOD1 mice.…”

Section: Discussionmentioning

confidence: 99%

Glycinergic Innervation of Motoneurons Is Deficient in Amyotrophic Lateral Sclerosis Mice

Chang

Martin

2009

The American Journal of Pathology

112

138

View full text Add to dashboard Cite

Altered motoneuron excitability is involved in amyotrophic lateral sclerosis pathobiology. To test the hypothesis that inhibitory interneuron innervation of spinal motoneurons is abnormal in an amyotrophic lateral sclerosis mouse model, we measured GABAergic, glycinergic, and cholinergic immunoreactive terminals on spinal motoneurons in mice expressing a mutant form of human superoxide dismutase-1 with a Gly933 Ala substitution (G93A-SOD1) and in controls at different ages. Glutamic acid decarboxylase, glycine transporter-2, and choline acetyltransferase were used as markers for GABAergic, glycinergic, and cholinergic terminals, respectively. Triple immunofluorescent labeling of boutons contacting motoneurons was visualized by confocal microscopy and analyzed quantitatively. Glycine transporter-2-bouton density on lateral motoneurons was decreased significantly in G93A-SOD1 mice compared with controls. This reduction was absent at 6 weeks of age but present in asymptomatic 8-week-old mice and worsened with disease progression from 12 to 14 weeks of age. Motoneurons lost most glycinergic innervation by 16 weeks of age (end-stage) when there was a significant decrease in the numbers of motoneurons and choline acetyltransferase-positive boutons. No significant differences in glutamic acid decarboxylase-bouton densities were found in G93A-SOD1 mice. Reduction of glycinergic innervation preceded mitochondrial swelling and vacuolization. Calbindin-positive Renshaw cell number was decreased significantly at 12 weeks of age in G93A-SOD1 mice. Thus, either the selective loss of inhibitory glycinergic regulation of motoneuron function or glycinergic interneuron degeneration contributes to motoneuron degeneration in amyotrophic lateral sclerosis. (Am J

show abstract

“…Paired-pulse TMS techniques have disclosed a marked reduction or absence of SICI in sporadic ALS cohorts that have been accompanied by an increase in ICF (Fig. 3A), which together are indicative of cortical hyperexcitability [85][86][87][88][89]. Importantly, features of cortical hyperexcitability, as heralded by reduced SICI, occur in the early stages of ALS, precede the clinical and neurophysiological onset of lower motor neuron dysfunction, and correlate with biomarkers of peripheral neurodegeneration [5,87,90].…”

Section: Alsmentioning

confidence: 96%

“…The notion that SICI reduction represents compensatory changes in response to lower motor neuron degeneration has also been suggested [86]. Given, however, that SICI changes were not evident ALS-mimicking disorders, despite a comparable peripheral disease burden [5,100], would argue against such a notion.…”

Section: Alsmentioning

confidence: 99%

Transcranial Magnetic Stimulation for the Assessment of Neurodegenerative Disease

Vucic

Kiernan

2017

Neurotherapeutics

View full text Add to dashboard Cite

Transcranial magnetic stimulation (TMS) is a noninvasive technique that has provided important information about cortical function across an array of neurodegenerative disorders, including Alzheimer's disease, frontotemporal dementia, Parkinson's disease, and related extrapyramidal disorders. Application of TMS techniques in neurodegenerative diseases has provided important pathophysiological insights, leading to the development of pathogenic and diagnostic biomarkers that could be used in the clinical setting and therapeutic trials. Abnormalities of TMS outcome measures heralding cortical hyperexcitability, as evidenced by a reduction of short-interval intracortical inhibition and increased in motorevoked potential amplitude, have been consistently identified as early and intrinsic features of amyotrophic lateral sclerosis (ALS), preceding and correlating with the ensuing neurodegeneration. Cortical hyperexcitability appears to form the pathogenic basis of ALS, mediated by trans-synaptic glutamate-mediated excitotoxic mechanisms. As a consequence of these research findings, TMS has been developed as a potential diagnostic biomarker, capable of identifying upper motor neuronal pathology, at earlier stages of the disease process, and thereby aiding in ALS diagnosis. Of further relevance, marked TMS abnormalities have been reported in other neurodegenerative diseases, which have varied from findings in ALS. With time and greater utilization by clinicians, TMS outcome measures may prove to be of utility in future therapeutic trial settings across the neurodegenerative disease spectrum, including the monitoring of neuroprotective, stem-cell, and genetic-based strategies, thereby enabling assessment of biological effectiveness at early stages of drug development.

show abstract

Different mechanisms contribute to motor cortex hyperexcitability in amyotrophic lateral sclerosis

Cited by 142 publications

References 44 publications

Hyperexcitability of Cultured Spinal Motoneurons From Presymptomatic ALS Mice

Hyperexcitability of Cultured Spinal Motoneurons From Presymptomatic ALS Mice

Glycinergic Innervation of Motoneurons Is Deficient in Amyotrophic Lateral Sclerosis Mice

Transcranial Magnetic Stimulation for the Assessment of Neurodegenerative Disease

Contact Info

Product

Resources

About