Prenatal inflammation alters the adult immune hippocampal microenvironment and impairs adult neurogenesis.in t he rat

MARIANA GRACIARENA; AMAICHA M DEPINO; FERNANDO J. PITOSSI

Congreso; ANNUAL MEETING OF THE ISSCR; 2009

ISSCR

Prenatal inflammation alters the adult immune hippocampal microenvironment and impairs adult neurogenesis.in t he rat M. GRACIARENA, D. BATTISTA, C. C. FERRARI, F. J. PITOSSI Leloir Foundation-CONICET, Buenos Aires, Argentina   The perinatal stage is characterized by increased sensitivity to certain stimuli that will be reflected in changes in adult physiology. In particular, prenatal exposure to lipopolysaccharide (LPS), a well known cytokine inducer, is important to determine later immune responses.In addition, we and others have observed that a change of the brain milleu to a pro-inflammatory scenario can diminish adult neurogenesis, highlighting the effects of endogenous brain cytokines as part of the neurogenic niche.We have hypothesized that a prenatal LPS challenge could alter the brain environment of endogenous neural stem cells and alter 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. In adulthood, at postnatal day 60, rats were injected with 50 mg/kg of bromodeoxyuridine (BrdU, intraperitoneal - i.p.) daily for 7 days.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). Proliferation and total progenitor cell population remained unchanged as measured by counting the number of Nestin-positive cells. 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-beta expression in the adult hippocampi of LPS-treated rats. Over-expression of TGF-beta in the adult hippocampi of prenatally LPS-treated rats not only reverted the decrease in adult neurogenesis but also return to basal levels the performance on a behavioural task associated with adult neurogenesis (Novel object recognition).We conclude that prenatal LPS challenge decreases adult neurogenesis and novel object recognition perfomance. This effect involves long lasting changes in the local microenvironment towards a pro- inflammatory milleu. TGF-beta plays a key role in the prenatally-induced decreases in adult neurogenesis.