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.