Pathological tau leads to network hyperexcitability through neuronal-subtype-specific functional impairment
- 1New York University Grossman School of Medicine
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.
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BibTeX
@misc{ji2026pathological,
title = {{Pathological tau leads to network hyperexcitability through neuronal-subtype-specific functional impairment}},
author = {C. Ji and Y. Zhu and H. Erdjument-Bromage and S. C. Song and N. Chang and A. R. Liu and A. R. Lee and O. DeGulis and D. Schoppik and T. A. Neubert and H. D. Ryoo and E. Sigurdsson},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.05.756807},
url = {https://www.biorxiv.org/content/10.64898/2026.10.05.756807v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Pathological tau leads to network hyperexcitability through neuronal-subtype-specific functional impairment
AU - C. Ji
AU - Y. Zhu
AU - H. Erdjument-Bromage
AU - S. C. Song
AU - N. Chang
AU - A. R. Liu
AU - A. R. Lee
AU - O. DeGulis
AU - D. Schoppik
AU - T. A. Neubert
AU - H. D. Ryoo
AU - E. Sigurdsson
PY - 2026
DA - 2026/10/05
PB - bioRxiv
DO - 10.64898/2026.10.05.756807
UR - https://www.biorxiv.org/content/10.64898/2026.10.05.756807v1
AB - 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.
ER -