Pathological tau leads to network hyperexcitability through neuronal-subtype-specific functional impairment
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.
Show 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.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- Immune receptor LAG3 regulates microglia function duringAlzheimer's disease 95%
- Tunable Tau Expression in C. elegans Neurons Reveals that Early-AD Tau Phosphorylation Selectively Impacts Behavior and Mitochondrial Quality Control 95%
- Regional interneuron transcriptional changes reveal pathologic markers of disease progression in a mouse model of Alzheimer's disease 93%
Similar papers in this journal
- Divergent and Convergent TMEM106B Pathology in Murine Models of Neurodegeneration and Human Disease 94%
- Retinal ganglion cell vulnerability to pathogenic tau in Alzheimer's disease 93%
- A post-translational modification signature defines changes in soluble tau correlating with oligomerization in early stage Alzheimer’s disease brain 93%