Parvalbumin interneurons in Alzheimer's disease: Physiological insights and pathophysiological mechanisms

Abstract

Fast-spiking parvalbumin-positive (PV⁺) interneurons, a specialized class of inhibitory neurons, possess unique morphological and functional properties that govern spatiotemporal precision in local microcircuits, large-scale network synchronization, and memory-related computations. Since their initial identification in the late 19th century, technological innovations in cellular neuroscience have progressively elucidated the multifaceted roles of these neurons. In this review, we first delineate the embryonic origins and developmental trajectory of PV⁺ interneurons, emphasizing their unique properties for high-frequency firing with remarkable temporal precision. These specialized features enable PV⁺ interneurons to orchestrate network oscillations and critically modulate memory encoding, consolidation, and retrieval, despite their substantial metabolic demands. We subsequently integrate multiple lines of evidence implicating region- and subtype-specific PV⁺ interneuron impairment as a pivotal pathological hallmark in Alzheimer's disease (AD). Furthermore, we dissect molecular and cellular mechanisms driving PV⁺ interneuron dysfunction in AD, including numerical alterations, morphological remodeling, and electrophysiological disruptions. Critically, we propose that the pathological transformation of PV⁺ interneuron physiology emerges as a key driver in AD progression, bridging cellular dysfunction to system-level cognitive failure.