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Induction of Toll-like receptor 3-mediated immunity during gestation inhibits cortical neurogenesis and causes behavioral disturbances

Joari De Miranda; Kavitha Yaddanapudi; Mady Hornig; Gabriel Villar; Robert G. Serge; W. Ian Lipkin

Title:
Induction of Toll-like receptor 3-mediated immunity during gestation inhibits cortical neurogenesis and causes behavioral disturbances
Author(s):
De Miranda, Joari
Yaddanapudi, Kavitha
Hornig, Mady
Villar, Gabriel
Serge, Robert G.
Lipkin, W. Ian
Date:
Type:
Articles
Department:
Center for Infection and Immunity
Volume:
1
Permanent URL:
Book/Journal Title:
mBio
Abstract:
Maternal infection during pregnancy with a wide range of RNA and DNA viruses is associated with increased risk for schizophrenia and autism in their offspring. A common feature in these exposures is that virus replication induces innate immunity through interaction with Toll-like receptors (TLRs). We employed a mouse model wherein pregnant mice were exposed to polyinosinic-polycytidylic acid [poly(I ⋅ C)], a synthetic, double-stranded RNA molecular mimic of replicating virus. Poly(I ⋅ C) inhibited embryonic neuronal stem cell replication and population of the superficial layers of the neocortex by neurons. Poly(I ⋅ C) also led to impaired neonatal locomotor development and abnormal sensorimotor gating responses in adult offspring. Using Toll-like receptor 3 (TLR3)-deficient mice, we established that these effects were dependent on TLR3. Inhibition of stem cell proliferation was also abrogated by pretreatment with the nonsteroidal anti-inflammatory drug (NSAID) carprofen, a cyclooxygenase (COX) inhibitor. Our findings provide insights into mechanisms by which maternal infection can induce subtle neuropathology and behavioral dysfunction, and they may suggest strategies for reducing the risk of neuropsychiatric disorders subsequent to prenatal exposures to pathogens and other triggers of innate immunity.
Subject(s):
Epidemiology
Virology
Publisher DOI:
10.1128/mBio.00176-10
Item views:
189
Metadata:
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