DIFFERENTIAL VULNERABILITY OF ADULT NEUROGENESIS BY ADULT AND PRENATAL INFLAMMATION: ROLE OF TGF-BETA1

VALERIA ROCA; MARIANA GRACIARENA; PATRICIA MATHIEU; FERNANDO PITOSSI

Boston, Mass

Congreso; ISSCR 11th Annual Meeting; 2013

International Society for Stem Cell Research

Peripheral inflammation impairs adult neurogenesis, both during the prenatal period and in the adulthood. We hypothesized that, similar to other programming effects of prenatal treatments, only prenatal inflammation causes long-term consequences in adult neurogenesis and its neurogenic niche. To test this, pregnant Wistar rats were subcutaneously injected with lipopolyssaccharide (LPS; 0.5mg/kg) or saline solution every other day from gestational/embryonic day (GD) 14 to 20. In addition adult animals were injected with a single intraperitoneal saline or LPS injection (1mg/kg) and the effects on neurogenesis were assessed 7 days later. Alternatively, to evaluate long-term consequences of adult LPS injections, LPS (1mg/kg) was administered peripherally to adult rats 4 times every other day, and the effects on neurogenesis were assessed 60 days later. Prenatal and adult LPS treatments reduced adult neurogenesis and provoke specific microglial (but not astroglial) activation in the DG. However, only prenatal inflammation-mediated effects were long-lasting (at least 60 days).Moreover, these effects were specific to the DG since the SVZ was not affected. In addition, these stimuli caused differential effects on the molecular components of the neurogenic niche; only prenatal LPS treatment reduced the local levels of TGF-β1 mRNA in the DG. In parallel, prenatal LPS also altered an adult neurogenesis-dependent behavioural task (Novel Object Recognition (NOR). When the reduced levels of TGF- β1 caused by prenatal LPS were increased by the adult administration of adenoviral vectors expressing this cytokine, adult neurogenesis levels and the performance in the NOR test were restored. Finally, TGF-β1 exerted its pro-neurogenic effects via the Smad2/3 pathway in a neural stem cell culture. Taken together, these data add evidence to the duration, regional specificity and dramatic consequences of prenatal immune programming on CNS physiology, compared with the limited response observed in the adult brain and highlight the role of TGF-β1 on adult neurogenesis and NOR.