Prefrontal parvalbumin interneurons deficits mediate early emotional dysfunction in Alzheimer's disease

Alzheimer's disease (AD) is the most common neurodegenerative disease and has an insidious onset. Exploring the characteristics and mechanism of the early symptoms of AD plays a critical role in the early diagnosis and intervention of AD. Here we found that depressive-like behavior and short-term spatial memory dysfunction appeared in APPswe/PS1dE9 mice (AD mice) as early as 9-11 weeks of age. Electrophysiological analysis revealed excitatory/inhibitory (E/I) imbalance in the prefrontal cortex (PFC). This E/I imbalance was induced by significant reduction in the number and activity of parvalbumin interneurons (PV⁺ INs) in this region. Furthermore, optogenetic and chemogenetic activation of residual PV⁺ INs effectively ameliorated depressive-like behavior and rescued short-term spatial memory in AD mice. These results suggest the PFC is selectively vulnerable in the early stage of AD and prefrontal PV⁺ INs deficits play a key role in the occurrence and development of early symptoms of AD.