Disrupted hippocampal replay is associated with reduced offline map stabilization in an Alzheimer's mouse model.

Abstract

Alzheimer's disease is characterized by progressive memory decline associated with hippocampal degeneration. However, the specific physiological mechanisms underlying hippocampal dysfunction in the disease remain poorly understood-improved knowledge may aid diagnosis and identify new avenues for therapeutic intervention. We investigated how disruptions in hippocampal reactivations relate to place cell stability and spatial memory deficits in an Alzheimer's mouse model. Using the App knockin mouse model NL-G-F, we conducted simultaneous behavioral and electrophysiological recordings in a radial arm maze. NL-G-F mice exhibited significant impairments in memory performance, demonstrated by an increased propensity to revisit arms, compared with wild-type controls. These memory deficits were associated with reduced stability of hippocampal place cells, which was particularly pronounced following rest periods. Crucially, although wild-type mice showed enhanced place cell stability after quiescence, NL-G-F mice failed to exhibit this consolidation. Although the rate of hippocampal reactivation events during rest remained unchanged, analysis of replay content revealed significantly degraded replay quality in NL-G-F mice. This degradation manifested as disrupted cell recruitment and reduced co-firing structure within reactivation events, both of which predicted the failure of offline place cell stabilization. Together, these findings suggest that compromised reactivation quality may underlie disruptions in offline consolidation processes, offering a potential mechanism for memory dysfunction in Alzheimer's disease.