Second trimester maternal infection and perinatal hypoxia are potent activators of the immune system and pro-inflammatory cytokines, which may affect normal brain development, thus predisposing for developing schizophrenia. In our recent brain expression profiling experiments of the prefrontal cortex of subjects with schizophrenia, we have uncovered a number of robust gene expression changes related to the immune response. These changes, verified by qPCR, suggest an inflammatory cytokine-induced transcriptome signature that include interferon-inducible (IFITM family), MHC class II (DP, DR and DQ classes), heat-shock proteins (HSP28 and HSP70), complement system (C1 and C3) and other transcripts. In addition, virtually all high-density microarray studies of schizophrenia to date have reported expression changes related to the immune system. Animal studies also support a strong link between biological changes seen in schizophrenia and cytokine expression. In particular, prenatal treatment of rats or mice with a single dose of the synthetic cytokine inducer polyriboinosinic-polyribocytidilic acid [poly(l:C)] leads to postpubertal emergence of disrupted latent inhibition, prepulse inhibition (PPI), dopaminergic hyperfunction and brain pathology in the offspring. This suggests that viral infection is not necessary;the maternal immune response appears to be key in causing changes in fetal brain development. Based on these findings we hypothesize that various environmental influences, via pro-inflammatory cytokine induction, trigger a strong transcriptome response in the developing brain that may persist into adult life. To test this hypothesis, we will design comprehensive immune custom DMA microarrays for mouse and human (Aim 1) and analyze the immune transcriptome of prefrontal cortex (PFC), superior temporal gyrus (STG) and cerebellum (CBL) in 30 subjects with schizophrenia and matched controls (Aim 2). Furthermore, we will assess transcriptome changes in the corresponding brain regions of mice treated at various time points with poly(l:C) (Aim 3). After identification of the common gene expression changes across the human and mouse datasets (Aim 4) we will verify by qPCR and localize to cell type by in situ hybridization the most promising gene expression changes (Aim 5). We predict that subjects with schizophrenia will show consistently altered expression of specific immune response genes that are directly regulated by pro-inflammatory cytokines, and that some of these expression changes will also be observed in the brain of adolescent/adult mice that were exposed to poly(l:C)-mediated cytokine induction during embryonic life. These commonly observed immune transcript changes between the human tissue and mouse model(s) will help us define a testable molecular substrate by which environmental influences predispose for developing schizophrenia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH079299-04
Application #
7775052
Study Section
Special Emphasis Panel (ZRG1-BDCN-A (90))
Program Officer
Meinecke, Douglas L
Project Start
2007-03-12
Project End
2012-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
4
Fiscal Year
2010
Total Cost
$344,420
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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