Impaired parvalbumin interneurons in the retrosplenial cortex as the cause of sex-dependent vulnerability in Alzheimer’s disease

Abstract

Alzheimer's Disease is a common and debilitating neurodegenerative disorder with no cure and few treatment options. Impaired metabolism in the retrosplenial cortex during prodromal stages of the disease has been proposed as a strong predictor of future cognitive impairments. The retrosplenial cortex is also one of the earlier brain regions to exhibit functional impairments in Alzheimer's Disease. Therefore, understanding Alzheimer's related deficits in the retrosplenial cortex may be critical in understanding the origins of cognitive impairment and could provide early treatment targets. Here, we investigated alterations in retrosplenial cortex structure and function in a mouse model of Alzheimer's Disease. We identified a novel sex dependent early impairment in parvalbumin-interneuron activity which, is sufficient to induce cognitive impairments and, dysregulate functional connectivity of the retrosplenial cortex. Reversal of cognitive deficits by stimulation of parvalbumin interneurons in retrosplenial cortex suggests that this may serve as a promising novel therapeutic strategy.