IMMUNE SIGNALS AS PART OF THE ADULT NEUROGENIC NICHE

FERNANDO J PITOSSI

Congreso; congreso la sociedad de terapia celular; 2010

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) and activated microglial cells till stage 3. 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, blockade of TGF-b functional activity in the adult hippocampus diminished neurogenesis in vivo, indicating a pro-neurogenic role of TGF-b. Moreover, TGF-b  was able to promote neurogenesis in NSC primary cultures directly. This enhanced neurogenesis was blocked by Smad7-expressing adenoviral vectors. We have also hypothesized that a prenatal LPS challenge could alter the brain environment of endogenous neural stem cells and modify adult neurogenesis. To test this hypothesis, we injected Wistar pregnant rats subcutaneously with LPS (0,5 mg/kg) or saline at embryonic days 14, 16, 18 and 20. We observed significantly reduced adult neurogenesis levels in prenatally LPS-treated rats compared to controls, as assessed by co-labeling of BrdU and neuronal markers (PSA-NCAM; DCX or NeuN). This effect was specific for the differentiation but not the proliferation of NSC or the survival of newborn neurons. Moreover, adult microglial activation was observed only in the prenatally LPS-treated group. Maternal care or the neuroendocrine responses seem not to contribute to the changes in adult neurogenesis observed. Cytokine expression analysis by real-time RT-PCR revealed a decrease in TGF-b expression in the adult hippocampus of LPS-treated rats. Over-expression of TGF-b in the adult hippocampus of prenatally LPS-treated rats not only reverted the decrease in adult neurogenesis but also return to basal levels the performance on a behavioral task associated with adult neurogenesis (Novel object recognition). We conclude that prenatal LPS challenge decreases adult neurogenesis and novel object recognition performance. TGF-b plays a key role in the prenatally-induced decreases in adult neurogenesis and its associated changes in behavior. In all, these data plays microglia and immune cytokines such as TGF-beta as functional components of the adult neurogenic niche.