Increased levels of midbrain immune-related transcripts in schizophrenia and in murine offspring after maternal immune activation
Open Access
- 5 June 2019
- journal article
- research article
- Published by Springer Science and Business Media LLC in Molecular Psychiatry
- Vol. 26 (3), 849-863
- https://doi.org/10.1038/s41380-019-0434-0
Abstract
The pathophysiology of dopamine dysregulation in schizophrenia involves alterations at the ventral midbrain level. Given that inflammatory mediators such as cytokines influence the functional properties of midbrain dopamine neurons, midbrain inflammation may play a role in schizophrenia by contributing to presynaptic dopamine abnormalities. Thus, we quantified inflammatory markers in dopaminergic areas of the midbrain of people with schizophrenia and matched controls. We also measured these markers in midbrain of mice exposed to maternal immune activation (MIA) during pregnancy, an established risk factor for schizophrenia and other psychiatric disorders. We found diagnostic increases in SERPINA3, TNFα, IL1β, IL6, and IL6ST transcripts in schizophrenia compared with controls (p < 0.02–0.001). The diagnostic differences in these immune markers were accounted for by a subgroup of schizophrenia cases (~ 45%, 13/28) showing high immune status. Consistent with the human cohort, we identified increased expression of immune markers in the midbrain of adult MIA offspring (SERPINA3, TNFα, and IL1β mRNAs, all p ≤ 0.01), which was driven by a subset of MIA offspring (~ 40%, 13/32) with high immune status. There were no diagnostic (human cohort) or group-wise (mouse cohort) differences in cellular markers indexing the density and/or morphology of microglia or astrocytes, but an increase in the transcription of microglial and astrocytic markers in schizophrenia cases and MIA offspring with high inflammation. These data demonstrate that immune-related changes in schizophrenia extend to dopaminergic areas of the midbrain and exist in the absence of changes in microglial cell number, but with putative evidence of microglial and astrocytic activation in the high immune subgroup. MIA may be one of the contributing factors underlying persistent neuroimmune changes in the midbrain of people with schizophrenia.Funding Information
- Department of Health | National Health and Medical Research Council (1117079)
This publication has 70 references indexed in Scilit:
- The hCMEC/D3 cell line as a model of the human blood brain barrierFluids and Barriers of the CNS, 2013
- Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophreniaMolecular Psychiatry, 2012
- Gene Expression Analysis Implicates a Death Receptor Pathway in Schizophrenia PathologyPLOS ONE, 2012
- Antipsychotic Dose Equivalents and Dose-Years: A Standardized Method for Comparing Exposure to Different DrugsBiological Psychiatry, 2010
- Selection of Reference Gene Expression in a Schizophrenia Brain CohortAustralian & New Zealand Journal of Psychiatry, 2010
- The Dopamine Hypothesis of Schizophrenia: Version III--The Final Common PathwaySchizophrenia Bulletin, 2009
- Molecular Evidence for Increased Expression of Genes Related to Immune and Chaperone Function in the Prefrontal Cortex in SchizophreniaBiological Psychiatry, 2007
- Effects of cytokines and infections on brain neurochemistryClinical Neuroscience Research, 2006
- Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophreniaNature Neuroscience, 2002
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001