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

Abstract

Early hippocampal hyperactivity is a well-documented yet poorly defined phenomenon in Alzheimers disease (AD). While reported in both patients and animal models, its functional manifestations and underlying neurophysiological mechanisms in vivo remain unclear. Here, we address this gap using in vivo high-resolution patch-clamp, high-throughput single-unit, and local field recordings in young amyloidopathy mice, at a stage when A{beta} remains largely soluble. We uncover previously unidentified cellular mechanisms in vivo, characterised by reduced inhibitory synaptic input, hypoactivity of fast-spiking interneurons, and enhanced bursting in pyramidal neurons. At the network level, we reveal accelerated hippocampal oscillations, marked by increased theta and beta power, a departure from the conventional view of oscillation slowing in AD. Mechanistically, this acceleration stems from strengthened synchrony of excitatory currents at higher frequencies and an overall reduction in oscillation-associated inhibitory currents. Our findings provide the first direct in vivo evidence linking early hippocampal hyperactivity to specific synaptic transmission and network dysfunctions, resolving a long-standing ambiguity. Moreover, we propose accelerated oscillations in the hippocampus as a functional biomarker for early AD and a potential therapeutic target for restoring network stability before cognitive decline occurs.