Activation of a latent hippocampal precursor population

Abstract

Adult neurogenesis, the generation of new, functional neurons, occurs in two main niches within the adult mammalian brain⎯the dentate gyrus of the hippocampus (DG) and the subventricular zone (SVZ) of the lateral ventricle. We have previously shown that the hippocampus contains a population of quiescent neural stem and precursor cells which can be activated by mimicking neural activity (depolarisation with KCl in vitro). Interestingly, depolarisation of the SVZ precursor cells has the opposite effect, indicating that the stem cells in the two neurogenic niches appear to be under very different regulatory control. To better understand the differences between the two neurogeneic zones, we compared the transcript profiles of the neural precursor cells isolated from the SVZ and DG.  This revealed redox regulation to be particularly enriched in the DG neural precursor cells. Several redox-related proteins, including SelenoproteinP (SEPP1), were highly up-regulated in the DG.

SEPP1 is the major transporter of the trace element selenium from the plasma into the brain. Selenium is necessary for normal brain function and its deficiency is correlated with a number of neurodegenerative diseases. We show that selenium can directly activate latent hippocampal precursor cells and increase neuronal differentiation in vitro, and increase both proliferation and net neurogenesis in vivo. Furthermore, we show that this effect is likely mediated by selenium's antioxidative properties, functioning to reduce levels of ferroptosis-mediated cell death and thus significantly reducing levels of reactive oxygen species, in a NOX2-dependent manner.