Increased Axon Initial Segment Length Results in Increased Na+ Currents in Spinal Motoneurones at Symptom Onset in the G127X SOD1 Mouse Model of Amyotrophic Lateral Sclerosis

Jörgensen, H; Jensen, Dennis Bo; Dimintiyanova, Kristina Petrova; Bonnevie, Veronika S; Hedegaard, Anne; Lehnhoff, Janna; Moldovan, Mihai; Grøndahl, Lillian; Meehan, Claire Francesca

doi:10.1016/j.neuroscience.2020.11.016

Cited by 27 publications

(53 citation statements)

References 102 publications

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“…This hypothesis is supported by our observations in the G127X mouse model of ALS where the axon initial segments of the spinal motoneurones increase in length upon symptom onset (Jørgensen et al . 2020), similar to our observations following spinal cord injury (Dimintiyanova et al . 2016).…”

Section: Discussionsupporting

confidence: 93%

“…2020; Jørgensen et al . 2020). We also saw signs of an increased responsiveness to input seen as a decrease in rheobase and an increased f – I gain.…”

Section: Discussionmentioning

confidence: 99%

“…Na + PICs presumably arise from the area with the highest density of Nav 1.6 channels, the axon initial segment, which has been shown to increase in length at symptom onset in the G127X model (Jørgensen et al . 2020). These would already be partially activated subspike threshold and so, as noted earlier, would be critical for kicking off repetitive firing.…”

Section: Discussionmentioning

confidence: 99%

“…This is highly relevant because excitability changes are observed with disease progression in the G127X SOD1 mouse (Jørgensen et al . 2020).…”

Section: Introductionmentioning

confidence: 99%

“…The present study therefore aimed to repeat our previous studies that we performed in the G127X SOD1 mouse (Jørgensen et al . 2020), but this time using the same G93A SOD1 model and anaesthetic as Delestree et al . (2014) and Martinez‐Silva et al .…”

Section: Introductionmentioning

confidence: 99%

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Spinal motoneurones are intrinsically more responsive in the adult G93A SOD1 mouse model of amyotrophic lateral sclerosis

Jensen

Kadlecova

Allodi

et al. 2020

The Journal of Physiology

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Although in vitro recordings using neonatal preparations from mouse models of amyotrophic lateral sclerosis (ALS) suggest increased motoneurone excitability, in vivo recordings in adult ALS mouse models have been conflicting. r In adult G93A SOD1 models, spinal motoneurones have previously been shown to have deficits in repetitive firing, in contrast to the G127X SOD1 mouse model. r Our in vivo intracellular recordings in barbiturate-anaesthetized adult male G93A SOD1 mice reveal that the incidence of failure to fire with current injection was equally low in control and ALS mice (ß2%). r We show that failure to fire repetitively can be a consequence of experimental protocol and should not be used alone to classify otherwise normal motoneurones as hypo-excitable. r Motoneurones in the G93A SOD1 mice showed an increased response to inputs, with lower rheobase, higher input-output gains and increased activation of persistent inward currents.

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Section: Discussionsupporting

confidence: 93%

“…2020; Jørgensen et al . 2020). We also saw signs of an increased responsiveness to input seen as a decrease in rheobase and an increased f – I gain.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…This is highly relevant because excitability changes are observed with disease progression in the G127X SOD1 mouse (Jørgensen et al . 2020).…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Spinal motoneurones are intrinsically more responsive in the adult G93A SOD1 mouse model of amyotrophic lateral sclerosis

Jensen

Kadlecova

Allodi

et al. 2020

The Journal of Physiology

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Neurofilament accumulations in amyotrophic lateral sclerosis patients’ motor neurons impair axonal initial segment integrity

Lefebvre-Omar,

Liu,

Dalle

et al. 2023

Cell. Mol. Life Sci.

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Amyotrophic lateral sclerosis (ALS) is the most common motor neuron (MN) disease in adults with no curative treatment. Neurofilament (NF) level in patient’ fluids have recently emerged as the prime biomarker of ALS disease progression, while NF accumulation in MNs of patients is the oldest and one of the best pathological hallmarks. However, the way NF accumulations could lead to MN degeneration remains unknown. To assess NF accumulations and study the impact on MNs, we compared MNs derived from induced pluripotent stem cells (iPSC) of patients carrying mutations in C9orf72, SOD1 and TARDBP genes, the three main ALS genetic causes. We show that in all mutant MNs, light NF (NF-L) chains rapidly accumulate in MN soma, while the phosphorylated heavy/medium NF (pNF-M/H) chains pile up in axonal proximal regions of only C9orf72 and SOD1 MNs. Excitability abnormalities were also only observed in these latter MNs. We demonstrate that the integrity of the MN axonal initial segment (AIS), the region of action potential initiation and responsible for maintaining axonal integrity, is impaired in the presence of pNF-M/H accumulations in C9orf72 and SOD1 MNs. We establish a strong correlation between these pNF-M/H accumulations, an AIS distal shift, increased axonal calibers and modified repartition of sodium channels. The results expand our understanding of how NF accumulation could dysregulate components of the axonal cytoskeleton and disrupt MN homeostasis. With recent cumulative evidence that AIS alterations are implicated in different brain diseases, preserving AIS integrity could have important therapeutic implications for ALS.

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Aberrant axon initial segment plasticity and intrinsic excitability of ALS hiPSC motor neurons

Harley,

Kerins,

Gatt

et al. 2023

Cell Reports

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Increased Axon Initial Segment Length Results in Increased Na+ Currents in Spinal Motoneurones at Symptom Onset in the G127X SOD1 Mouse Model of Amyotrophic Lateral Sclerosis

Cited by 27 publications

References 102 publications

Spinal motoneurones are intrinsically more responsive in the adult G93A SOD1 mouse model of amyotrophic lateral sclerosis

Spinal motoneurones are intrinsically more responsive in the adult G93A SOD1 mouse model of amyotrophic lateral sclerosis

Neurofilament accumulations in amyotrophic lateral sclerosis patients’ motor neurons impair axonal initial segment integrity

Aberrant axon initial segment plasticity and intrinsic excitability of ALS hiPSC motor neurons

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