Electric activity changes in human glutamatergic derived neurons with tau isoform imbalances.

Tauopathies are a heterogeneous group of neurodegenerative diseases characterized by abnormal metabolism of tau protein, driving alterations in synaptic, ion channel activity, neuronal dysfunction and death. A key feature of the tau gene (MAPT) is generation of two isoform groups differing in microtubule-binding repeats: three repeats (3R) or four repeats (4R), expressed at a 1:1 ratio in the adult human brain. A hallmark of several tauopathies is a shift in this ratio, seen in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), with predominance of 4R tau, or in Pick's disease, with increased 3R tau. Our group previously showed that changes in the 3R/4R ratio regulate axonal transport of APP vesicles, which may affect other cargoes that impair channel distribution and synaptic function. To gain insight into the physiological role of these isoform-specific regulations, we shifted neurons towards 3R or 4R tau and performed calcium imaging using Fluo-3 AM dye in iPSC-derived glutamatergic neurons at day in vitro 25 (DIV25). A customized imaging pipeline was developed to extract frequency, duration, and amplitude of calcium transients. Preliminary results suggest increased 3R/4R ratio raises the frequency of calcium events. In conclusion, these results indicate tau isoform composition plays a key role in regulating neuronal electrical activity and maturation, suggesting disease-associated isoform imbalances may disrupt neuronal network function in the brain