Forced Physical Training Increases Neuronal Proliferation and Maturation with Their Integration into Normal Circuits in Pilocarpine Induced Status Epilepticus Mice

Abstract

Increased number of newly-born neurons produced at latent stage after status epilepticus (SE) contribute to aberrant rewiring of hippocampus and are hypothesized to promote epileptogenesis. Although physical training (PT) was reported to cause further increase in neurogenesis after SE, how PT affect their integration pattern is still elusive, whether they integrate into normal circuits or increase aberrant integrations is yet to be determined. To understand this basic mechanism by which PT effects SE and to elaborate the possible role of neuronal integrations in prognosis of SE, we evaluated the effect of 4 weeks of treadmill PT in adult male mice after pilocarpine-induced SE on behavioral and aberrant integrations' parameters. Changes in BDNF gene methylation and its protein level in hippocampus was also measured at latent stage (2-weeks) to explore underlying pathways involved in increasing neurogenesis. Our results demonstrated that although PT increased proliferation and maturation of neurons in dentate gyrus, they showed reduced aberrant integrations into hippocampal circuitry assessed through a decrease in the number of ectopic granular cells, hilar basal dendrites and mossy fiber sprouting as compared to non-exercised SE mice. While SE decreased the percentage methylation of specific CpGs of BDNF gene's promoter, PT did not yield any significant difference in methylation of BDNF CpGs as compared to non-exercised SE mice. In conclusion, PT increases hippocampal neurogenesis through increasing BDNF levels by some pathways other than demethylating BDNF CpGs and causes post SE newly-born neurons to integrate into normal circuits thus resulting in decreased spontaneous recurrent seizures and enhanced spatial memory.

Keywords: Aberrant hippocampal neurogenesis; Epilepsy; Exercise; Neurogenesis; Treadmill running.