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

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. HIGHLIGHTS The FTD-causing P301L tau mutation leads to neuronal network hyperexcitability. P301L tau causes hyperactivity of excitatory neurons while hypoactivity of inhibitory neurons. Tau and P301L tau interactomes differ in excitatory vs. inhibitory neurons. Enhanced excitatory synaptic transmission and P301L tau/AHNAK interaction in inhibitory neurons contribute to neuronal network hyperexcitability. Graphic Summary