Neuronal Excitability
The excitability properties of MNs are also implicated in the selective degeneration of specific MN subtypes in ALS. Alterations in MN excitability have been reported during the asymptomatic disease stage in the SOD1G93A (Saxena et al., 2013), s-SOD1G93A (Pambo-Pambo et al., 2009) and SOD1G85R (Bories et al., 2007) mouse models, in iPSC-derived MNs (Vucic et al., 2008; Wainger et al., 2014) and in SALS and FALS patients (Vucic and Kiernan, 2010; Devlin et al., 2015). Specific isoforms of the sodium–potassium pump (Na+/K+ATPase), which generates the Na+/K+ gradients that drive the action potential, are associated with the specific vulnerability of MN subtypes. Misfolded mutant SOD1 forms a complex with the α3 isoform of Na+/K+ATPase, and this leads to impairment in its ATPase activity. Altered levels of this isoform were also observed in spinal cords of SALS and non-SOD1 FALS patients (Ruegsegger et al., 2016). Importantly, α3 is the major isoform in vulnerable FF-MNs, whereas both α1 and α3 predominate in FR-MNs, and S-MNs express only α2. Furthermore, viral-mediated expression of a mutant Na+/K+ATPase-α3 that cannot bind to mutant SOD1 restored Na+/K+ATPase-α3 activity, delayed disease manifestations and increased lifespan in two different mutant SOD1 mouse models (SOD1G93A and SOD1G37R) (Ruegsegger et al., 2016). This indicates that modulating the activity of the α3 isoform of the Na+/K+ATPase, and therefore modulating the excitability status of MNs, is important in neurodegeneration in ALS.
However, increasing MN excitability is also neuroprotective to MNs in ALS. Enhancing MN excitability by delivering AMPA receptor agonists to mutant SOD1G93A mice reversed misfolded mutant protein accumulation, delayed pathology and extended survival, whereas reducing MN excitability by antagonist CNQX accelerated disease and induced early denervation, even in the more resistant S-MNs (Saxena et al., 2013). However, MN subpopulations can be differentially affected by changes in excitability. Disease resistant S-MNs exhibit hyper-excitability in ALS patients (de Carvalho and Swash, 2017) and early in disease in mutant SOD1G93A mice, whereas disease vulnerable FF-MNs are not hyper-excitable, again highlighting increased excitability as a protective property in ALS (Leroy et al., 2014). Also, the vulnerable masticatory trigeminal MNs from SOD1G93A mice exhibit a heterogeneous discharge pattern, unlike oculomotor neurons (Venugopal et al., 2015). However, MNs in FALS and SALS patients are hyperexcitable early in disease course, but then later become hypo-excitable (Vucic et al., 2008; Menon et al., 2015), indicating that modulation of neuronal excitability is a factor influencing the development of ALS.