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

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 HO, 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.