Inhibition of phosphodiesterase-5 rescues age-related impairment of synaptic plasticity and memory

Aging is characterized by a progressive cognitive decline that leads to memory impairment. Because the cyclic nucleotide cascade is essential for the integrity of synaptic function and memory, and it is down-regulated during aging and in neurodegenerative disorders, we investigated whether an increase in cGMP levels might rescue age-related synaptic and memory deficits in mice. We demonstrated that acute perfusion with the phosphodiesterase-5 inhibitor sildenafil (50 nM) ameliorated long-term potentiation in hippocampal slices from 26–30-month-old mice. Moreover, chronic intraperitoneal injection of sildenafil (3 mg/kg for 3 weeks) improved age-related spatial learning and reference memory as tested by the Morris Water Maze, and recognition memory as tested by the Object Recognition Test. Finally, sildenafil restored central cAMP responsive element-binding protein (CREB) phosphorylation, which is crucial for synaptic plasticity and memory. Our data suggest that inhibition of phosphodiesterase-5 may be beneficial to treat age-related cognitive dysfunction in a physiological mouse model of aging.

► We used 26–30 months-old wild type mice as a physiological model of aging. ► We analyzed hippocampal basal synaptic transmission and long-term potentiation. ► We analyzed spatial learning, reference and recognition memory. ► Sildenafil improved synaptic function and memory in aged mice. ► Sildenafil restored central CREB phosphorylation in old mice.