Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout development
Maternal infection is a risk factor for autism spectrum disorder (ASD) and schizophrenia (SZ). Indeed, modeling this risk factor in mice through maternal immune activation (MIA) causes ASD- and SZ-like neuropathologies and behaviors in the offspring. Although MIA upregulates pro-inflammatory cytokines in the fetal brain, whether MIA leads to long-lasting changes in brain cytokines during postnatal development remains unknown. Here, we tested this possibility by measuring protein levels of 23 cytokines in the blood and three brain regions from offspring of poly(I:C)- and saline-injected mice at five postnatal ages using multiplex arrays. Most cytokines examined are present in sera and brains throughout development. MIA induces changes in the levels of many cytokines in the brains and sera of offspring in a region- and age-specific manner. These MIA-induced changes follow a few, unexpected and distinct patterns. In frontal and cingulate cortices, several, mostly pro-inflammatory, cytokines are elevated at birth, followed by decreases during periods of synaptogenesis and plasticity, and increases again in the adult. Cytokines are also altered in postnatal hippocampus, but in a pattern distinct from the other regions. The MIA-induced changes in brain cytokines do not correlate with changes in serum cytokines from the same animals. Finally, these MIA-induced cytokine changes are not accompanied by breaches in the blood–brain barrier, immune cell infiltration or increases in microglial density. Together, these data indicate that MIA leads to long-lasting, region-specific changes in brain cytokines in offspring—similar to those reported for ASD and SZ—that may alter CNS development and behavior.
© 2012 Elsevier Inc. Available online 25 July 2012. We are grateful for the advice of several immunologists at U.C. Davis in the experimental design and interpretation of this study, including Drs. Judy van de Water, Paul Ashwood, and Nicole Baumgarth. Myka Estes also helped in editing the manuscript. This work was supported by an ARRA grant from the National Institutes of Mental Health (NIMH) R01-MH088879 (AKM), an R01 from the National Eye Institute (NEI) R01-EY13584 (AKM), a supplement to support Paula Garay (R01-EY13584-S1; AKM), NIMH grant 5R01 MH079299 (K. Mirnics and PHP), an NRSA pre-doctoral fellowship from NIMH (EYH), and a Dennis Weatherstone fellowship from Autism Speaks (EYH).
Accepted Version - nihms401516.pdf
Supplemental Material - mmc1.docx
Supplemental Material - mmc2.docx