Hypoexcitability precedes denervation in the large fast-contracting motor units in two unrelated mouse models of ALS

Martínez-Silva, María de Lourdes; Imhoff-Manuel, Rebecca D; Sharma, Aarti; Heckman, C. J.; Shneider, Neil A.; Roselli, Francesco; Zytnicki, Daniel; Manuel, Marin

doi:10.7554/elife.30955

Cited by 119 publications

(178 citation statements)

References 57 publications

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“…Therefore, it appears that post-synaptic inhibitions are probably reduced in ALS, which would have the opposite effect on F-D compared to those we report. As a consequence, we propose that the reduction of F-D in patients is probably related to depressed intrinsic excitability of spinal motoneurons, as reported in animal models (Delestrée et al 2014;Martínez-Silva et al 2018).…”

Section: Pathophysiological Interpretationssupporting

confidence: 65%

“…; Martínez‐Silva et al . ). In our experiments, it is possible that larger PICs compensated for a reduced descending and peripheral inputs (Iglesias et al .…”

Section: Discussionmentioning

confidence: 97%

“…Data analyses were performed taking into account all the motor unit pairs collected in the two protocols because motoneurons can manifest different sensitivities to PICs (Cotel et al 2009;Wilson et al 2015) and they can be differentially altered in ALS (Nijssen et al 2017;Martínez-Silva et al 2018). Moreover, we also compared F-D between subjects (controls vs. patients with ALS); the maximal F-D observed in each muscle in each individual subject was considered when several motor unit pairs were collected.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study has reported that the most sensitive motoneurons to degeneration (innervating fast motor units) are hypoexcitable, whereas the most resilient motoneurons (innervating slow motor units) exhibit normal excitability (Martínez‐Silva et al . ). Studies of human motoneurons derived from induced pluripotent stem cells (iPSCs) have confirmed similar stages in excitability (Wainger et al .…”

Section: Introductionmentioning

confidence: 97%

“…Reports of excitability are inconsistent in superoxide dismutase 1 (SOD1) mutant mice, ranging from hyperexcitability in embryos (Pieri et al 2003;Kuo et al 2005;Martin et al 2013) to hypoexcitability in presymptomatic adults (Delestrée et al 2014). A recent study has reported that the most sensitive motoneurons to degeneration (innervating fast motor units) are hypoexcitable, whereas the most resilient motoneurons (innervating slow motor units) exhibit normal excitability (Martínez-Silva et al 2018). Studies of human motoneurons derived from induced pluripotent stem cells (iPSCs) have confirmed similar stages in excitability (Wainger et al 2014;Devlin et al 2015;Naujock et al 2016).…”

Section: Introductionmentioning

confidence: 99%

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Absence of hyperexcitability of spinal motoneurons in patients with amyotrophic lateral sclerosis

Marchand‐Pauvert

Peyre

Lackmy-Vallée

et al. 2019

The Journal of Physiology

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Key points •Amyotrophic lateral sclerosis (ALS) motoneurons become hypoexcitable with disease progression in experimental models, raising questions about the neural hyperexcitability supported by clinical observations. •A variant of the ∆F method, based on motor unit discharge frequency modulations during recruitment and derecruitment, has been developed to investigate the motoneuron capacity to self‐sustained discharge in patients. •The modulation of motor unit firing rate during ramp contraction and vibration‐induced recruitment are modified in ALS, suggesting lower motoneuron capacity to self‐sustained discharge, which is a sign of hypoexcitability. •∆F‐D decreases with functional impairment and its reduction is more pronounced in fast progressors. •In patients with ALS, motoneurons exhibit hypoexcitability, which increases with disease progression. Abstract Experimental models have primarily revealed spinal motoneuron hypoexcitability in amyotrophic lateral sclerosis (ALS), which is contentious considering the role of glutamate‐induced excitotoxicity in neurodegeneration and clinical features rather supporting hyperexcitability. This phenomenon was evaluated in human patients by investigating changes in motor unit firing during contraction and relaxation. Twenty‐two ALS patients with subtle motor deficits and 28 controls performed tonic contractions of extensor carpi radialis, triceps brachialis, tibialis anterior and quadriceps, aiming to isolate a low‐threshold unit (U1) on the electromyogram (EMG). Subsequently, they performed a stronger contraction or tendon vibration was delivered, to recruit higher threshold unit (U2) for 10 s before they relaxed progressively. EMG and motor unit potential analyses suggest altered neuromuscular function in all muscles, including those with normal strength (Medical Research Council score at 5). During the preconditioning tonic phase, U1 discharge frequency did not differ significantly between groups. During recruitment, the increase in U1 frequency (∆F‐R) was comparable between groups both during contraction and tendon vibration. During derecruitment, the decrease in U1 frequency (∆F‐D) was reduced in ALS regardless of the recruitment mode, particularly for ∆F‐R <8 Hz in the upper limbs, consistent with the muscle weakness profile of the group. ∆F‐D was associated with functional disability and its reduction was more pronounced in patients with more rapid disease progression rate. This in vivo study has demonstrated reduced motoneuron capacity for self‐sustained discharge, and further supports that motoneurons are normo‐ to hypoexcitable in ALS patients, similar to observations in experimental models.

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Section: Pathophysiological Interpretationssupporting

confidence: 65%

“…; Martínez‐Silva et al . ). In our experiments, it is possible that larger PICs compensated for a reduced descending and peripheral inputs (Iglesias et al .…”

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Absence of hyperexcitability of spinal motoneurons in patients with amyotrophic lateral sclerosis

Marchand‐Pauvert

Peyre

Lackmy-Vallée

et al. 2019

The Journal of Physiology

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Amyotrophic Lateral Sclerosis: Fuel for the Corticofugal Feud

Wainger

Brown

2020

Annals of Neurology

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Astrocyte‐targeting RNA interference against mutated superoxide dismutase 1 induces motoneuron plasticity and protects fast‐fatigable motor units in a mouse model of amyotrophic lateral sclerosis

Rochat

Bernard-Marissal

Källstig

et al. 2022

Glia

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In amyotrophic lateral sclerosis (ALS) caused by SOD1 gene mutations, both cellautonomous and noncell-autonomous mechanisms lead to the selective degeneration of motoneurons (MN). Here, we evaluate the therapeutic potential of gene therapy targeting mutated SOD1 in mature astrocytes using mice expressing the mutated SOD1 G93A protein. An AAV-gfaABC 1 D vector encoding an artificial microRNA is used to deliver RNA interference against mutated SOD1 selectively in astrocytes. The treatment leads to the progressive rescue of neuromuscular junction occupancy, to the recovery of the compound muscle action potential in the gastrocnemius muscle, and significantly improves neuromuscular function. In the spinal cord, gene therapy targeting astrocytes protects a small pool of the most vulnerable fast-fatigable MN until disease end stage. In the gastrocnemius muscle of the treated SOD1 G93A mice, the fast-twitch type IIB muscle fibers are preserved from atrophy. Axon collateral sprouting is observed together with muscle fiber type grouping indicative of denervation/reinnervation events. The transcriptome profiling of spinal cord MN shows changes in the expression levels of factors regulating the dynamics of microtubules. Gene therapy delivering RNA interference against mutated SOD1 in astrocytes protects fast-fatigable motor units and thereby improves neuromuscular function in ALS mice.

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Hypoexcitability precedes denervation in the large fast-contracting motor units in two unrelated mouse models of ALS

Cited by 119 publications

References 57 publications

Absence of hyperexcitability of spinal motoneurons in patients with amyotrophic lateral sclerosis

Absence of hyperexcitability of spinal motoneurons in patients with amyotrophic lateral sclerosis

Amyotrophic Lateral Sclerosis: Fuel for the Corticofugal Feud

Astrocyte‐targeting RNA interference against mutated superoxide dismutase 1 induces motoneuron plasticity and protects fast‐fatigable motor units in a mouse model of amyotrophic lateral sclerosis

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