Increased Levels of Midbrain Immune-related Transcripts in Schizophrenia and in Murine Offspring After Maternal Immune Activation

Overview

Journal Mol Psychiatry

Specialties Molecular Biology
Psychiatry

Date 2019 Jun 7

PMID 31168068

Citations 51

Authors

Tertia D Purves-Tyson

Ulrike Weber-Stadlbauer

Juliet Richetto

Debora A Rothmond

Marie A Labouesse

Marcello Polesel

Kate Robinson

Cynthia Shannon Weickert

Urs Meyer

Affiliations

Soon will be listed here.

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.

Citing Articles

Maternal immune activation followed by peripubertal stress combinedly produce reactive microglia and confine cerebellar cognition.

Hikosaka M, Parvez M, Yamawaki Y, Oe S, Liang Y, Wada Y Commun Biol. 2025; 8(1):296.

PMID: 40033126 PMC: 11876345. DOI: 10.1038/s42003-025-07566-2.

Neurodevelopmental and Neuropsychiatric Disorders.

Traetta M, Chaves Filho A, Akinluyi E, Tremblay M Adv Neurobiol. 2024; 37:457-495.

PMID: 39207708 DOI: 10.1007/978-3-031-55529-9_26.

Maternal prenatal immune activation associated with brain tissue microstructure and metabolite concentrations in newborn infants.

Spann M, Bansal R, Aydin E, Pollatou A, Alleyne K, Bennett M Brain Behav Immun. 2024; 122:279-286.

PMID: 39163912 PMC: 11551918. DOI: 10.1016/j.bbi.2024.08.025.

Differential effects of purified low molecular weight Poly(I:C) in the maternal immune activation model depend on the laboratory environment.

Tillmann K, Schaer R, Mueller F, Mueller K, Voelkl B, Weber-Stadlbauer U Transl Psychiatry. 2024; 14(1):300.

PMID: 39033141 PMC: 11271296. DOI: 10.1038/s41398-024-03014-7.

Prenatal Immune Challenge Differentiates the Effect of Aripiprazole and Risperidone on CD200-CD200R and CX3CL1-CX3CR1 Dyads and Microglial Polarization: A Study in Organotypic Cortical Cultures.

Chamera K, Curzytek K, Kaminska K, Leskiewicz M, Basta-Kaim A Life (Basel). 2024; 14(6).

PMID: 38929704 PMC: 11205240. DOI: 10.3390/life14060721.

References

Zhang Y, Catts V, Sheedy D, McCrossin T, Kril J, Weickert C . Cortical grey matter volume reduction in people with schizophrenia is associated with neuro-inflammation. Transl Psychiatry. 2016; 6(12):e982. PMC: 5290336. DOI: 10.1038/tp.2016.238. View

Felger J, Miller A . Cytokine effects on the basal ganglia and dopamine function: the subcortical source of inflammatory malaise. Front Neuroendocrinol. 2012; 33(3):315-27. PMC: 3484236. DOI: 10.1016/j.yfrne.2012.09.003. View

Woods S . Chlorpromazine equivalent doses for the newer atypical antipsychotics. J Clin Psychiatry. 2003; 64(6):663-7. DOI: 10.4088/jcp.v64n0607. View

Benveniste E . Inflammatory cytokines within the central nervous system: sources, function, and mechanism of action. Am J Physiol. 1992; 263(1 Pt 1):C1-16. DOI: 10.1152/ajpcell.1992.263.1.C1. View

Meyer-Lindenberg A, Miletich R, Kohn P, Esposito G, Carson R, Quarantelli M . Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci. 2002; 5(3):267-71. DOI: 10.1038/nn804. View

Vuillermot S, Weber L, Feldon J, Meyer U . A longitudinal examination of the neurodevelopmental impact of prenatal immune activation in mice reveals primary defects in dopaminergic development relevant to schizophrenia. J Neurosci. 2010; 30(4):1270-87. PMC: 6633802. DOI: 10.1523/JNEUROSCI.5408-09.2010. View

Holmes S, Hinz R, Drake R, Gregory C, Conen S, Matthews J . In vivo imaging of brain microglial activity in antipsychotic-free and medicated schizophrenia: a [C](R)-PK11195 positron emission tomography study. Mol Psychiatry. 2016; 21(12):1672-1679. DOI: 10.1038/mp.2016.180. View

Meyer U . Prenatal poly(i:C) exposure and other developmental immune activation models in rodent systems. Biol Psychiatry. 2013; 75(4):307-15. DOI: 10.1016/j.biopsych.2013.07.011. View

Fillman S, Weickert T, Lenroot R, Catts S, Bruggemann J, Catts V . Elevated peripheral cytokines characterize a subgroup of people with schizophrenia displaying poor verbal fluency and reduced Broca's area volume. Mol Psychiatry. 2015; 21(8):1090-8. PMC: 4960447. DOI: 10.1038/mp.2015.90. View

10.

Brown A, Derkits E . Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry. 2010; 167(3):261-80. PMC: 3652286. DOI: 10.1176/appi.ajp.2009.09030361. View

11.

Baumeister D, Ciufolini S, Mondelli V . Effects of psychotropic drugs on inflammation: consequence or mediator of therapeutic effects in psychiatric treatment?. Psychopharmacology (Berl). 2015; 233(9):1575-89. DOI: 10.1007/s00213-015-4044-5. View

12.

Weksler B, Romero I, Couraud P . The hCMEC/D3 cell line as a model of the human blood brain barrier. Fluids Barriers CNS. 2013; 10(1):16. PMC: 3623852. DOI: 10.1186/2045-8118-10-16. View

13.

Cotel M, Lenartowicz E, Natesan S, Modo M, Cooper J, Williams S . Microglial activation in the rat brain following chronic antipsychotic treatment at clinically relevant doses. Eur Neuropsychopharmacol. 2015; 25(11):2098-107. DOI: 10.1016/j.euroneuro.2015.08.004. View

14.

Richetto J, Chesters R, Cattaneo A, Labouesse M, Gutierrez A, Wood T . Genome-Wide Transcriptional Profiling and Structural Magnetic Resonance Imaging in the Maternal Immune Activation Model of Neurodevelopmental Disorders. Cereb Cortex. 2016; 27(6):3397-3413. DOI: 10.1093/cercor/bhw320. View

15.

Meyer U, Feldon J, Fatemi S . In-vivo rodent models for the experimental investigation of prenatal immune activation effects in neurodevelopmental brain disorders. Neurosci Biobehav Rev. 2009; 33(7):1061-79. DOI: 10.1016/j.neubiorev.2009.05.001. View

16.

Acarin L, Gonzalez B, Castellano B . Neuronal, astroglial and microglial cytokine expression after an excitotoxic lesion in the immature rat brain. Eur J Neurosci. 2000; 12(10):3505-20. DOI: 10.1046/j.1460-9568.2000.00226.x. View

17.

Fillman S, Sinclair D, Fung S, Webster M, Weickert C . Markers of inflammation and stress distinguish subsets of individuals with schizophrenia and bipolar disorder. Transl Psychiatry. 2014; 4:e365. PMC: 3944638. DOI: 10.1038/tp.2014.8. View

18.

Hagihara H, Catts V, Katayama Y, Shoji H, Takagi T, Huang F . Decreased Brain pH as a Shared Endophenotype of Psychiatric Disorders. Neuropsychopharmacology. 2017; 43(3):459-468. PMC: 5770757. DOI: 10.1038/npp.2017.167. View

19.

Hadar R, Soto-Montenegro M, Gotz T, Wieske F, Sohr R, Desco M . Using a maternal immune stimulation model of schizophrenia to study behavioral and neurobiological alterations over the developmental course. Schizophr Res. 2015; 166(1-3):238-47. PMC: 5233455. DOI: 10.1016/j.schres.2015.05.010. View

20.

Zuckerman L, Rehavi M, Nachman R, Weiner I . Immune activation during pregnancy in rats leads to a postpubertal emergence of disrupted latent inhibition, dopaminergic hyperfunction, and altered limbic morphology in the offspring: a novel neurodevelopmental model of schizophrenia. Neuropsychopharmacology. 2003; 28(10):1778-89. DOI: 10.1038/sj.npp.1300248. View