Reduced inhibition, bursting, and accelerated oscillations drive early hippocampal hyperactivity in Alzheimer's disease in vivo.

'Early hippocampal hyperactivity' is well-documented in Alzheimer's disease (AD), yet its mechanisms in vivo before amyloid-β plaque deposition at the levels of synaptic transmission and neural oscillations remain unclear. Here, we perform in vivo high-resolution patch-clamp and high-throughput probe recordings in the hippocampus of amyloidopathy mice before plaque deposition. At the cellular level, we observe reduced inhibitory synaptic input, hypoactivity of fast-spiking interneurons, and enhanced bursting in pyramidal neurons. At the network level, we reveal accelerated hippocampal oscillations, characterized by increased theta and beta power. Mechanistically, this acceleration stems from selectively strengthened synchrony of oscillation-associated excitatory synaptic currents at higher frequencies. Our findings provide in vivo evidence linking early hippocampal hyperactivity to specific alterations in synaptic transmission dynamics and network dysfunction, highlighting that accelerated oscillations in the hippocampus could be a functional biomarker for early AD and a therapeutic target for restoring network stability before cognitive decline occurs.