Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease defined by the selective loss of motor neurons. TDP-43 pathology, with cytoplasmic mislocalization and phosphorylation, is found in ~97% of cases, and TDP-43 mutations, including Q331K and M337V, are linked to ALS. Excitotoxic calcium overload is a leading candidate mechanism for motor neuron death, because these cells combine low calcium buffering with strong calcium entry through calcium-permeable AMPA receptors (CP-AMPAR). Two routes to CP-AMPAR expression have been proposed. Whether the above TDP-43 mutations engage either route in human motor neurons is not known. Here, we asked whether these mutations alter AMPA and NMDA receptor expression, TDP-43 pathology, CP-AMPAR-dependent calcium entry, and whether that entry can be blocked pharmacologically.