Abstract
Increases in axonal sodium currents in peripheral nerves are some of the earliest excitability changes observed in Amyotrophic Lateral Sclerosis (ALS) patients. Nothing is known, however, about axonal sodium channels more proximally, particularly at the action potential initiating region - the axon initial segment (AIS). Immunohistochemistry for Nav1.6 sodium channels was used to investigate parameters of AISs of spinal motoneurones in the G127X SOD1 mouse model of ALS in adult mice at presymptomatic time points (~190 days old). In vivo intracellular recordings from lumbar spinal motoneurones were used to determine the consequences of any AIS changes. AISs of both alpha and gamma motoneurones were found to be significantly shorter (by 6.6% and 11.8% respectively) in G127X mice as well as being wider by 9.8% (alpha motoneurones). Measurements from 20–23 day old mice confirmed that this represented a change during adulthood. Intracellular recordings from motoneurones in presymptomatic adult mice, however, revealed no differences in individual action potentials or the cells ability to initiate repetitive action potentials. To conclude, despite changes in AIS geometry, no evidence was found for reduced excitability within the functional working range of firing frequencies of motoneurones in this model of ALS.
Highlights
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease which preferentially affects motoneurones in the brain and spinal cord
In the current experiments we focus on central sodium channels in the same transgenic mouse model at pre-symptomatic adult time points with a particular focus on the axon initial segment (AIS)
AISs of alpha motoneurones were slightly (6.6%) but significantly shorter in the G127X mice (Fig. 1C). When this data is displayed as cumulative frequency fractions it can be seen that this difference is not due to a selective loss at one end of the distribution but an overall shift of all values in the G127X mice towards shorter lengths (Fig. 1D)
Summary
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease which preferentially affects motoneurones in the brain and spinal cord. In vitro investigations of cultured motoneurones from the transgenic G93A SOD1 mouse model of the disease have shown increases in persistent sodium currents[23,24] with sodium channels displaying a faster recovery from fast inactivation than controls[25]. Our previous in vivo investigations in the adult G127X SOD1 mouse model of ALS have confirmed a presymptomatic increase in Na+ current in distal peripheral motor axons[27] and a disruption of axonal potassium channels related to a breakdown of nodal organisation in the ventral roots of these mice, assumed to be indicative of axonal degeneration[28]. In the current experiments we focus on central sodium channels in the same transgenic mouse model at pre-symptomatic adult time points with a particular focus on the axon initial segment (AIS). In the present experiments immunohistochemistry was used to label Nav1.6 sodium channels at AISs of spinal motoneurones in adult presymptomatic G127X SOD1 mice combined with in vivo intracellular recording to identify the functional significance of any changes
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