TDP-43 Mutation Organoid Electrophysiology

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases characterized by the aggregation and cytoplasmic mislocalization of TDP-43, a protein encoded by TARDBP that normally regulates pre-mRNA processing in the nucleus. In addition to protein aggregation, altered neuronal excitability is a hallmark of disease pathology, with early hyperexcitability followed by progressive hypoexcitability. However, the electrophysiological consequences of TDP-43 dysfunction remain underexplored in complex 3D models. This study investigates the electrophysiological properties of cortical and spinal cord organoids with the TARDBP I383V mutation using calcium imaging and microelectrode arrays. By comparing mutant organoids to isogenic controls, this work aims to characterize how neuronal firing patterns change over developmental time and to determine whether organoid models recapitulate disease-associated excitability phenotypes