Treadmill exercise improves behavioral outcomes and spatial learning memory through up-regulation of reelin signaling pathway in autistic rats

Autism is a complex neurodevelopmental disability with impairments of social interaction and communication, and repetitive behavior. Reelin is an extracellular glycoprotein that is essential for neuronal migration and brain development. Neuroprotective effects of exercise on various brain insults are well documented, however, the effects of exercise on autism in relation with reelin expression are not clarified. In the present study, we investigated the effects of treadmill exercise on the functional recovery and on the expressions of reelin and its downstream molecules, phosphatidylinositol-3-kinase (PI3K), phosphorylated Akt (p-Akt), phosphorylated extracellular signal-regulated protein kinase 1 and 2 (p-ERK1/2), using autistic rats. For the induction of autism-like animal model, 400 mg/kg valproic acid was subcutaneously injected into the rats on the postnatal day 14. The rat in the treadmill exercise groups were forced to run on a treadmill for 30 min once a day, five times a week for 4 weeks, starting postnatal day 28. To investigate autism-like behaviors and memory deficit, open field, social interaction, and radial 8-arm maze were performed. Immunohistochemistry and western blotting were conducted. In the present results, treadmill exercise alleviated aggressive tendency and improved correct decision in the spatial learning memory in the autistic rats. Treadmill exercise increased neurogenesis and the expressions of reelin and its down-stream molecules, PI3K, p-Akt, and p-ERK1/2, in the hippocampus of the autistic rats. The present study showed that treadmill exercise ameliorated aggressive behavior and improved spatial learning memory through activation of reeling signaling pathway in the valproic acid-induced autistic rats.