Chronic mild hypoxia promotes hippocampal neurogenesis involving Notch1 signaling in epileptic rats

Cognitive impairment is one of the most common and disabling co-morbidities of epilepsy. It is therefore imperative to find novel treatment approaches to rescue cognitive function among epilepsy patients. Adult neurogenesis is strongly implicated in cognitive function, and mild hypoxia is known to promote the proliferation and differentiation of both embryonic and adult neural stem cells (NSCs). In the present study, we investigated the effect of mild hypoxia on cognitive function and hippocampal neurogenesis of rats with pilocarpine-induced chronic epilepsy. Chronic epilepsy induced marked spatial learning and memory deficits in the Morris water maze that were rescued by consecutively 28 days mild hypoxia exposure (6 h/d at 3000 m altitude equivalent) during the chronic phase. Moreover, mild hypoxia reversed the suppression of hippocampal neurogenesis and the downregulation of NT-3 and BDNF expression in hippocampus and cortex of epileptic rats. Mild hypoxia in vitro also promoted hippocampus-derived NSC proliferation and neuronal differentiation. In addition, mild hypoxia enhanced Notch1 and Hes1 expression, suggesting that Notch1 signaling may be involved in neuroprotection of hypoxia. Our data may help to pave the way for identifying new therapeutic targets for rescuing cognition conflicts in epileptic patients by using hypoxia to promote hippocampus neurogenesis.