Abstract
BackgroundPhysical 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 FindingsTo 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/SignificanceExercise 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.
Highlights
It is well accepted that cell proliferation and neurogenesis continue to occur in selected brain regions of the adult brain, notably the subgranular zone of the dentate gyrus (DG) and the subventricular zone of the lateral ventricles [1]
We showed that inhibiting PI3K by infusion of LY294002 prevents exercise-induced phosphorylation of these proteins and stems exercise-induced neurogenesis in the dentate gyrus without affecting cell proliferation
Certain regulators of proliferation and survival of newborn cells have been identified, that include growth factors and morphogens, hormones, certain neurotransmitters, intracellular signaling molecules and transcription factors [1]. Much of this knowledge derives from studies in cell cultures, while the mechanisms associated with neurogenesis in the intact, behaving animal remain poorly defined
Summary
It is well accepted that cell proliferation and neurogenesis continue to occur in selected brain regions of the adult brain, notably the subgranular zone of the dentate gyrus (DG) and the subventricular zone of the lateral ventricles [1]. Exercise exerts a beneficial effect on spatial learning [2,11,12] and some studies have associated the exercised-induced improvement in learning with its ability to promote neurogenesis and to facilitate long-term potentiation (LTP) in the dentate gyrus [13,14]. LTP was facilitated in parallel with the increase in neurogenesis in control runners and inhibition of the PI3K completely blocked facilitation of LTP in association with the reduction in the number of surviving cells Taken together, these data represent a step forward in the identification of the prosurvival role of the PI3K-Akt pathway in regulating neurogenesis in the adult dentate gyrus
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