Progressive remote memory decline coincides with parvalbumin interneuron hyperexcitability and enhanced inhibition of cortical engram cells in a mouse model of Alzheimer’s disease

Abstract Patients with Alzheimer’s disease (AD) initially show temporally-graded retrograde amnesia, which gradually progresses into more severe retrograde amnesia. Although mouse models of AD have provided insight into neurobiological mechanisms contributing to impaired formation and retrieval of new memories, the process underlying the progressive loss of remote memories in AD has remained elusive. Here, we demonstrate age-dependent remote memory decline in APP/PS1 mice, which coincides with progressive hyperexcitability of parvalbumin (PV) interneurons in the medial prefrontal cortex (mPFC). Analysis of Fos expression showed that the remote memory deficit is not mirrored by changes in reactivation of memory-encoding neurons, so-called engram cells, nor PV interneuron (re)activation, in the mPFC. However, inhibitory input is enhanced onto engram cells compared to non-engram cells specifically in APP/PS1 mice. Our data indicate that age-dependent remote memory impairment in APP/PS1 mice is due to increased innervation of cortical engram cells by hyperexcitable PV interneurons, suggesting that dysfunctional inhibitory microcircuits in the neocortex mediate progressive retrograde amnesia in AD. Competing Interest Statement The authors have declared no competing interest. Footnotes ↵* Shared senior authors New experiments added to show amyloid load in the mPFC of APP/PS1 mice. Additional data analyses performed for cellular (re)activation experiments. Discussion restructured to avoid redundancies.