TRANSIENT ACTIVATION OF HIPPOCAMPAL PV NEURONS INDUCES LONG-LASTING COGNITIVE RESCUE IN A MOUSE MODEL OF ALZHEIMER’S DISEASE

Accumulating evidence indicates that life experiences and environmental complexity can protect against cognitive decline induced by Alzheimer’s disease (AD). This phenomenon, known as cognitive reserve, delays the clinical expression of the pathology, yet its underlying neuronal substrate remains poorly understood.
Previous studies have demonstrated that a transient 10-day exposure to an enriched environment (EE), rich in sensory, cognitive, and social stimuli, preserves hippocampal-dependent memory in the Tg2576 mouse model of AD. This cognitive benefit is associated with increased activity of hippocampal parvalbumin (PV) inhibitory (GABAergic) neurons which are linked to abnormal brain activity and memory deficits associated with AD.
In this study, we tested whether activation of PV neurons is sufficient to reproduce the beneficial effects of EE on memory. To this end, we selectively and chronically activated hippocampal PV neurons for 10 days with DREADD (AAV-E2-hM3Dq), and assessed memory performance after a 20-day washout period.
Remarkably, 6-month-old Tg2576 mice displayed a robust recovery of hippocampal-dependent spatial memory that persisted 20 days after PV neuron activation, demonstrating that a temporary increase in PV neuron activity is sufficient to induce durable cognitive improvement.
Together, our findings show that transient activation of hippocampal PV neurons induces long-lasting cognitive rescue in a mouse model of AD, supporting the role of these neurons in mechanisms underlying cognitive reserve. By stabilizing hippocampal networks and supporting memory function, PV neuron activation may delay the emergence of cognitive deficits in AD, offering new insights into experience-dependent resilience mechanisms and potential therapeutic targets in AD.