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

Abstract

Memory deficits in Alzheimer's disease (AD) show a strong link with GABAergic interneuron dysfunctions.^{1,2,3,4,5,6,7} The ensemble dynamics of GABAergic interneurons represent memory encoding and retrieval,^8,9,10,11,12 but how GABAergic interneuron dysfunction affects inhibitory ensemble dynamics in AD is unknown. As the retrosplenial cortex (RSC) is critical for episodic memory^13,14,15,16 and is affected by β-amyloid accumulation in early AD,^{17,18,19,20,21} we address this question by performing Ca²⁺ imaging in RSC parvalbumin (PV)-expressing interneurons during a contextual fear memory task in healthy control mice and the 5XFAD mouse model of AD. We found that populations of PV interneurons responsive to aversive electric foot shocks during contextual fear conditioning (shock-responsive) significantly decreased in the 5XFAD mice, indicating dysfunctions in the recruitment of memory-encoding PV interneurons. In the control mice, ensemble activities of shock-responsive PV interneurons were selectively upregulated during the freezing epoch of the contextual fear memory retrieval, manifested by synaptic potentiation of PV interneuron-mediated inhibition. However, such changes in ensemble dynamics during memory retrieval and synaptic plasticity were both absent in the 5XFAD mice. Optogenetic silencing of PV interneurons during contextual fear conditioning in the control mice mimicked the memory deficits in the 5XFAD mice, while optogenetic activation of PV interneurons in the 5XFAD mice restored memory retrieval. These results demonstrate the critical roles of contextual fear memory-encoding PV interneurons for memory retrieval. Furthermore, synaptic dysfunction of PV interneurons may disrupt the recruitment of PV interneurons and their ensemble dynamics underlying contextual fear memory retrieval, subsequently leading to memory deficits in AD.

Keywords: Alzheimer's disease; calcium imaging; inhibitory engrams; inhibitory ensemble dynamics; parvalbumin-expressing interneurons; retrosplenial cortex.