Anesthesia‐induced hippocampal‐cortical hyperactivity and tau hyperphosphorylation impair remote memory retrieval in Alzheimer's disease

Abstract

AbstractINTRODUCTIONAnesthesia often exacerbates memory recall difficulties in individuals with Alzheimer's disease (AD), but the underlying mechanisms remain unclear.METHODSWe used in vivo Ca2+ imaging, viral‐based circuit tracing, and chemogenetic approaches to investigate anesthesia‐induced remote memory impairment in mouse models of presymptomatic AD.RESULTSOur study identified pyramidal neuron hyperactivity in the anterior cingulate cortex (ACC) as a significant contributor to anesthesia‐induced remote memory impairment. This ACC hyperactivation arises from the disinhibition of local inhibitory circuits and increased excitatory inputs from the hippocampal CA1 region. Inhibiting hyperactivity in the CA1‐ACC circuit improved memory recall after anesthesia. Moreover, anesthesia led to increased tau phosphorylation in the hippocampus, and inhibiting this hyperphosphorylation prevented ACC hyperactivity and subsequent memory impairment.DISCUSSIONHippocampal‐cortical hyperactivity plays a role in anesthesia‐induced remote memory impairment. Targeting tau hyperphosphorylation shows promise as a therapeutic strategy to mitigate anesthesia‐induced neural network dysfunction and retrograde amnesia in AD.