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
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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. / Jørgensen, H. S.; Jensen, D. B.; Dimintiyanova, K. P.; Bonnevie, V. S.; Hedegaard, A.; Lehnhoff, J.; Moldovan, M.; Grondahl, L.; Meehan, C. F.
In: Neuroscience, Vol. 468, 2021, p. 247-264.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - 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
AU - Jørgensen, H. S.
AU - Jensen, D. B.
AU - Dimintiyanova, K. P.
AU - Bonnevie, V. S.
AU - Hedegaard, A.
AU - Lehnhoff, J.
AU - Moldovan, M.
AU - Grondahl, L.
AU - Meehan, C. F.
PY - 2021
Y1 - 2021
N2 - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease preferentially affecting motoneurones. Transgenic mouse models have been used to investigate the role of abnormal motoneurone excitability in this disease. Whilst an increased excitability has repeatedly been demonstrated in vitro in neonatal and embryonic preparations from SOD1 mouse models, the results from the only studies to record in vivo from spinal motoneurones in adult SOD1 models have produced conflicting findings. Deficits in repetitive firing have been reported in G93A SOD1((high copy number)) mice but not in presymptomatic G127X SOD1 mice despite shorter motoneurone axon initial segments (AISs) in these mice. These discrepancies may be due to the earlier disease onset and prolonged disease progression in G93A SOD1 mice with recordings potentially performed at a later sub-clinical stage of the disease in this mouse. To test this, and to explore how the evolution of excitability changes with symptom onset we performed in vivo intracellular recording and AIS labelling in G127X SOD1 mice immediately after symptom onset. No reductions in repetitive firing were observed showing that this is not a common feature across all ALS models. Immunohistochemistry for the Na+ channel Nav1.6 showed that motoneurone AISs increase in length in G127X SOD1 mice at symptom onset. Consistent with this, the rate of rise of AIS components of antidromic action potentials were significantly faster confirming that this increase in length represents an increase in AIS Na+ channels occurring at symptom onset in this model. (C) 2020 Published by Elsevier Ltd on behalf of IBRO.
AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease preferentially affecting motoneurones. Transgenic mouse models have been used to investigate the role of abnormal motoneurone excitability in this disease. Whilst an increased excitability has repeatedly been demonstrated in vitro in neonatal and embryonic preparations from SOD1 mouse models, the results from the only studies to record in vivo from spinal motoneurones in adult SOD1 models have produced conflicting findings. Deficits in repetitive firing have been reported in G93A SOD1((high copy number)) mice but not in presymptomatic G127X SOD1 mice despite shorter motoneurone axon initial segments (AISs) in these mice. These discrepancies may be due to the earlier disease onset and prolonged disease progression in G93A SOD1 mice with recordings potentially performed at a later sub-clinical stage of the disease in this mouse. To test this, and to explore how the evolution of excitability changes with symptom onset we performed in vivo intracellular recording and AIS labelling in G127X SOD1 mice immediately after symptom onset. No reductions in repetitive firing were observed showing that this is not a common feature across all ALS models. Immunohistochemistry for the Na+ channel Nav1.6 showed that motoneurone AISs increase in length in G127X SOD1 mice at symptom onset. Consistent with this, the rate of rise of AIS components of antidromic action potentials were significantly faster confirming that this increase in length represents an increase in AIS Na+ channels occurring at symptom onset in this model. (C) 2020 Published by Elsevier Ltd on behalf of IBRO.
KW - Na+ channels
KW - axon initial segment
KW - ALS
KW - ACTIVITY-DEPENDENT RELOCATION
KW - MOTOR UNIT LOSS
KW - EXCITABILITY CHANGES
KW - SYNAPTIC-TRANSMISSION
KW - ELECTRICAL-PROPERTIES
KW - LUMBAR MOTONEURONS
KW - CORD-INJURY
KW - TIME-COURSE
KW - RILUZOLE
KW - ASTROCYTES
U2 - 10.1016/j.neuroscience.2020.11.016
DO - 10.1016/j.neuroscience.2020.11.016
M3 - Journal article
C2 - 33246068
VL - 468
SP - 247
EP - 264
JO - Neuroscience
JF - Neuroscience
SN - 0306-4522
ER -
ID: 275323865