TARDBP and amyotrophic lateral sclerosis: In the present study, we have undertaken detailed, temporal electrophysiological analyses of human iPSC-derived MNs, to investigate whether MN dysfunction represents an early feature of ALS pathogenesis common to neurons carrying mutations in TARDBP and C9ORF72. We demonstrate the development of appropriate functional properties in both control and patient iPSC-derived MNs but reveal a progressive loss of action potential output, spontaneous synaptic activity and ionic conductances in patient-derived MNs, regardless of their genotype, which occurs before any overt changes in cell viability.