Nox4 Promotes Neural Stem/Precursor Cell Proliferation and Neurogenesis in the Hippocampus and Restores Memory Function Following Trimethyltin-Induced Injury

Abstract

Reactive oxygen species (ROS) modulate the growth of neural stem/precursor cells (NS/PCs) and participate in hippocampus-associated learning and memory. However, the origin of these regulatory ROS in NS/PCs is not fully understood. In the present study, we found that Nox4, a ROS-producing NADPH oxidase family protein, is expressed in primary cultured NS/PCs and in those of the adult mouse brain. Nox inhibitors VAS 2870 and GKT137831 or Nox4 deletion attenuated bFGF-induced proliferation of cultured NS/PCs, while lentivirus-mediated Nox4 overexpression increased the production of H₂O₂, the phosphorylation of Akt, and the proliferation of cultured NS/PCs. Nox4 did not significantly affect the potential of cultured NS/PCs to differentiate into neurons or astrocytes. The histological and functional development of the hippocampus appeared normal in Nox4^-/- mice. Although pathological and functional damages in the hippocampus induced by the neurotoxin trimethyltin were not significantly different between wild-type and Nox4^-/- mice, the post-injury reactive proliferation of NS/PCs and neurogenesis in the subgranular zone (SGZ) of the dentate gyrus were significantly impaired in Nox4^-/- animals. Restoration from the trimethyltin-induced impairment in recognition and spatial working memory was also significantly attenuated in Nox4^-/- mice. Collectively, our findings suggest that Nox4 participates in NS/PC proliferation and neurogenesis in the hippocampus following injury, thereby helping to restore memory function.

Keywords: NADPH oxidase Nox4; hippocampus; learning and memory; neural stem/precursor cell; neurogenesis; proliferation.