Pathological tau leads to network hyperexcitability through neuronal-subtype-specific functional impairment

Authors

Ji, C., Zhu, Y., Erdjument-Bromage, H., Song, S. C., Chang, N., Liu, A. R., Lee, A. R., DeGulis, O., Schoppik, D., Neubert, T. A., Ryoo, H. D., Sigurdsson, E.

Abstract

Pathological tau disrupts neuronal activity and brain function in Alzheimer s disease and other tauopathies. However, the underlying mechanisms for neuronal network dysfunction remain largely unknown. Using human inducible pluripotent stem cell (iPSC) - derived neurons, we show that the familial MAPT P301L mutation leads to neuronal network hyperexcitability. Imbalanced excitation and inhibition were attributable to neuronal subtype-specific tau pathology that was associated with different alterations of tau interactomes in excitatory versus inhibitory neurons. Suppressing enhanced excitatory synaptic transmission or blocking Ca2+ influx resulting from enhanced P301L tau/AHNAK interaction in inhibitory neurons rescued the neuronal network hyperexcitability. This study expands our understanding on how disease-causing tau mutations alter the excitatory/inhibitory balance, leading to network dysfunction in human neurons.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 07 Oct 2026.

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