Mislocalized or mutant TDP-43 is suspected to play a major role in ALS pathogenesis (Buratti and Baralle, 2008; Sreedharan et al., 2008; Yokoseki et al., 2008), yet it is unclear how TDP-43 dysfunction or mutation is linked to altered cortical excitability. Here, TARDBP is linked to amyotrophic lateral sclerosis.