TARDBP and amyotrophic lateral sclerosis: As described above, cortical hyperexcitability is one of the main processes underlying ALS pathogenesis and it has been linked to synaptic alterations leading to overactivation of glutamate receptors, impaired inhibitory circuits, intrinsic motoneuron alterations, and astrocyte alterations; moreover, TDP-43 pathology may cause cell loss and synaptic alterations leading to compensatory hyperexcitability [87].