Neurogenic niche modulation by activated microglia: TGF-beta increases neurogenesis in vivo and in vitro

DANIELA BATTISTA; CARINA FERRARI; FRED GAGE; FERNANDO PITOSSI

Madrid

Congreso; 2º Congreso Iberoamericano de Neuroinmunomodulación; 2007

The environment is crucial for the regulation of the proliferation and differentiation of adult neural stem cells (NSC). We hypothesized that microglial cells and immune cytokines could be contributing to the adult neurogenic niche. We studied NSC proliferation and differentiation in an altered neurogenic niche by adrenal gland removal (ADX). ADX increased adult neurogenesis (as measured by the number of BrdU/PSA-NCAM-positive cells), incrementing the number of type-2 proliferating NSC in the dentate gyrus of the adult hippocampus. ADX also activated microglial cells till stage 3, but not to full-blown pro-inflammatory microglial activation. In addition, transforming growth factor beta (TGF-b) expression, but not Interleukin-1 or Tumor necrosis factor a was increased 10-fold in ADX animals. Interestingly, TGF-b expression co-localized with activated microglia and correlated with the amount of neurogenesis and activated microglia detected (r2= 0.99). In order to elucidate whether TGF-b could be participating in the increments in neurogenesis detected in our model, we blockade its functional activity by injection of neutralizing antibodies in the dentate gyrus of the adult hippocampus in ADX and sham-operated rats. This treatment diminished neurogenesis in vivo, indicating a pro-neurogenic role of TGF-b. Moreover, TGF-b  was able to directly promote neurogenesis in NSC primary cultures. In summary, we identified a define stage of microglial activation and TGF-bƒn productionƒz as functional components of the neurogenic niche in the adult brain.