Modulation of neural stem/progenitor cell proliferation during experimental Herpes Simplex encephalitis is mediated by differential FGF-2 expression in the adult brain

Abstract

Neural stem cells (NSCs) respond to inflammatory cues induced during brain injury and are thought to be involved in recovery from brain damage. Little is known about NSC response during brain infections. The present study evaluated NSC proliferation during Herpes Simplex Virus-1 brain infection. Total numbers of nestin(+) NSCs increased significantly in infected brains at 6days post infection (p.i.). However, by 15days p.i. the nestin(+) population decreased significantly below levels observed in uninfected brains and remained depressed through 30days p.i. This initial increase in NSC population occurred concurrently with increased brain cell proliferation, which peaked at 3days p.i. On closer examination, we found that while actively proliferating Sox2(+) NSCs increased in number at 6days p.i., proliferating DCX(+) neuroblasts contributed to the increased response at 3days p.i. However, overall proliferation decreased steadily from 15days p.i. to below control levels. To determine the mechanisms involved in altering NSC proliferation, neurotrophin and growth factor expression profiles were assessed. FGF-2 gene expression increased at 5days p.i. and was robustly down-regulated at 15days p.i. (>1000-fold), which was further confirmed by increased FGF-2 immunostaining around the lateral ventricles. Furthermore, supplementing infected animals with recombinant FGF-2, at 15days p.i., significantly increased the number of proliferating brain cells. These findings demonstrate that the temporal changes in NSC proliferation are mediated through the regulation of FGF-2 and that the NSC niche may benefit from supplementation with FGF-2 during HSV-1 brain infection.