mTORC2-Na_v1.2 signaling drives early hyperexcitability in Alzheimer's disease mouse model

Hyperexcitability is a biomarker of early-stage Alzheimer's Disease (AD) and hastens cognitive decline later in its course. Mechanistic target of rapamycin (mTOR) signaling contributes to the slope of this trajectory, as evidenced by early increased brain expression and the rescue of hyperexcitability by genetic deletion of mTOR complex 2 (mTORC2); however, a molecular mechanism directly linking mTOR signaling to membrane hyperexcitability in early-stage AD remains elusive. Here, we show that hyperactive mTOR signaling stimulates the voltage-gated Na⁺ channel 1.2 (Na_v1.2), a previously identified downstream phosphorylation target of mTORC2 and a key regulator of membrane electrogenesis. Augmented Na_v1.2 channel function induced by hyperactive mTOR signaling requires the action of mTORC2 and is selective among major brain Na_v channel isoforms. In a murine AD model, neocortical pyramidal neurons display augmented Na_v1.2 channel function and hyperexcitability through a mechanism that requires mTORC2 activity. These results highlight the mTORC2-Na_v1.2 interaction as a therapeutic target for attenuating pathogenic hyperexcitability in early-stage AD.