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Sharp-Wave Ripple Alterations Mark Memory Decline and Interneuron Drive


Hippocampal sharp-wave ripples (SWRs) – electrophysiological signatures of memory reactivation in the hippocampus – play an important role in memory processes. We tested the relationship between SWRs and memory impairment in an Alzheimer’s disease (AD) mouse model and the role of GABAergic interneurons in modulating SWRs. First, there is a pressing need to identify early pathophysiological alterations that predict subsequent memory impairment in AD. Mouse models of AD show reductions in both SWR abundance and associated slow gamma (SG) power during aging, suggesting SWRs may be a compelling candidate biomarker. In aged AD model mice, we found that reduced SWR abundance and associated CA3 SG power predicted spatial memory impairments measured 1–2 months later. Importantly, SWR-associated CA3 SG power reduction in young apoE4-KI mice also predicted spatial memory deficits measured 10 months later. Second, SWRs in CA1 are driven by inputs from upstream area CA3 and also engage the dentate gyrus (DG), but little is known about whether and how GABAergic interneurons in either CA3 or the DG regulate activity in CA1. The majority of hippocampal interneurons are parvalbumin-expressing (PV+), soma-targeting or somatostatin-expressing (SST+), distal dendrite-targeting subtypes, which are differentially impaired in AD. We find that that PV+ and SST+ interneurons bidirectionally modulate sleep SWRs in CA1 and coincident SG observed throughout the hippocampus. Overall, our results suggest that PV+ interneurons reduce CA3 coupling to CA1, while SST+ interneurons reduce entorhinal cortex coupling to CA1. These results establish features of SWRs as potential functional biomarkers of memory impairment in AD and probe how GABAergic interneuron subtypes impaired in AD modulate these SWR features.

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