Memory encoding and retrieval by retrosplenial parvalbumin interneurons is impaired in Alzheimer's disease model mice

Memory deficits in Alzheimers disease (AD) show a strong link with GABAergic interneuron dysfunctions1-7. Ensemble dynamics of GABAergic interneurons are critical in memory encoding and retrieval8-12 but how GABAergic interneuron dysfunction affects inhibitory ensemble dynamics in AD is unknown. As retrosplenial cortex (RSC) is a brain area critical for episodic memory13-16 and affected by beta-amyloid accumulation in early AD17-21, we address this question by performing Ca2+ imaging in RSC parvalbumin-expressing (PV) interneurons during a contextual fear memory (CFM) task in healthy control mice and the 5XFAD mouse model of AD. We found that subpopulations of PV interneurons that were responsive to aversive electric foot shocks during contextual fear conditioning (CFC) in the control mice significantly decreased in the 5XFAD mice, indicating a dysfunction in the recruitment of CFM-encoding PV interneurons. In control mice, CFC-responsive PV interneuron ensemble activities were selectively upregulated during the freezing epoch of the CFM retrieval, manifested by CFC-induced synaptic potentiation of PV interneuron-mediated inhibition. However, CFC-induced changes in PV interneuron ensemble dynamics during CFM retrieval and synaptic plasticity were both absent in the 5XFAD mice. Optogenetic silencing of PV interneurons during CFC in control mice mimicked the CFM deficits in 5XFAD mice, while optogenetic activation of PV interneurons during CFC in the 5XFAD mice restored CFM retrieval. These results demonstrate the necessity and sufficiency of CFC-responsive PV interneurons for CFM retrieval and suggest that synaptic dysfunction in CFM-encoding PV interneurons disrupt the inhibitory ensemble dynamics underlying CFM retrieval, subsequently leading to memory deficits in AD.