Inhibition of PI3K-Akt Signaling Blocks Exercise-Mediated Enhancement of Adult Neurogenesis and Synaptic Plasticity in the Dentate Gyrus

TLDR

Physical exercise increases adult neurogenesis and synaptic plasticity in the dentate gyrus. This study tests whether the PI3K‑Akt signaling pathway mediates exercise‑induced neurogenesis and synaptic plasticity. Rats received intracerebroventricular infusions of the PI3K inhibitor LY294002 or vehicle, exercised on a running wheel for 10 days, and were then evaluated for cell proliferation, neuronal survival, and LTP, with BrdU labeling and western blot analysis of Akt activation. Exercise enhanced proliferation and survival of newborn neurons and activated Akt and downstream targets, but LY294002 blocked Akt phosphorylation, had no effect on proliferation, yet eliminated the survival advantage and LTP increase, indicating PI3K‑Akt signaling is essential for exercise‑mediated neuronal survival and plasticity.

Abstract

Background Physical exercise has been shown to increase adult neurogenesis in the dentate gyrus and enhances synaptic plasticity. The antiapoptotic kinase, Akt has also been shown to be phosphorylated following voluntary exercise; however, it remains unknown whether the PI3K-Akt signaling pathway is involved in exercise-induced neurogenesis and the associated facilitation of synaptic plasticity in the dentate gyrus. Methodology/Principal Findings To gain insight into the potential role of this signaling pathway in exercise-induced neurogenesis and LTP in the dentate gyrus rats were infused with the PI3K inhibitor, LY294002 or vehicle control solution (icv) via osmotic minipumps and exercised in a running wheel for 10 days. Newborn cells in the dentate gyrus were date-labelled with BrdU on the last 3 days of exercise. Then, they were either returned to the home cage for 2 weeks to assess exercise-induced LTP and neurogenesis in the dentate gyrus, or were killed on the last day of exercise to assess proliferation and activation of the PI3K-Akt cascade using western blotting. Conclusions/Significance Exercise increases cell proliferation and promotes survival of adult-born neurons in the dentate gyrus. Immediately after exercise, we found that Akt and three downstream targets, BAD, GSK3β and FOXO1 were activated. LY294002 blocked exercise-induced phosphorylation of Akt and downstream target proteins. This had no effect on exercise-induced cell proliferation, but it abolished most of the beneficial effect of exercise on the survival of newly generated dentate gyrus neurons and prevented exercise-induced increase in dentate gyrus LTP. These results suggest that activation of the PI3 kinase-Akt signaling pathway plays a significant role via an antiapoptotic function in promoting survival of newly formed granule cells generated during exercise and the associated increase in synaptic plasticity in the dentate gyrus.