Increased levels of midbrain immune-related transcripts in schizophrenia and in murine offspring after maternal immune activation

Purves-Tyson, Tertia; Weber‐Stadlbauer, Ulrike; Richetto, Juliet; Rothmond, Debora A.; Labouesse, Marie A.; Polesel, Marcello; Robinson, Kate; Weickert, Cynthia Shannon; Meyer, Urs

doi:10.1038/s41380-019-0434-0

Cited by 93 publications

(112 citation statements)

References 70 publications

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“…The dysregulation of this balance can damage the neurons, cause a deficit of interneurons, leading to alteration of oligodendrocytes and inhibition of gamma-aminobutyric acid (GABA) interneurons (Nedic Erjavec et al, 2018). IL-1b and IL-6 promoted dopaminergic transmission (Purves-Tyson et al, 2019).…”

Section: Inflammatory Processes and Astrocytesmentioning

confidence: 99%

Alterations of Astrocytes in the Context of Schizophrenic Dementia

et al. 2020

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The levels of the astrocyte markers (GFAP, S100B) were increased unevenly in patients with schizophrenia. Reactive astrogliosis was found in approximately 70% of patients with schizophrenia. The astrocytes play a major role in etiology and pathogenesis of schizophrenia. Astrocytes produce the components that altered in schizophrenia extracellular matrix system which are involved in inflammation, functioning of interneurons, glio-, and neurotransmitter system, especially glutamate system. Astrocytes activate the interneurons through glutamate release and ATP. Decreased expression of astrocyte glutamate transporters was observed in patients with schizophrenia. Astrocytes influence on N-methyl-d-aspartate (NMDA) receptors via Dserine, an agonist of the glycine-binding site of NMDA receptors, and kynurenic acid, an endogenous antagonist. NMDA receptors, on its turn, control the impulses of dopamine neurons. Therefore following theories of schizophrenia are proposed. They are a) activation of astrocytes for neuroinflammation, b) glutamate and dopamine theory, as astrocyte products control the activity of NMDA receptors, which influence on the dopamine neurons.

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Section: Inflammatory Processes and Astrocytesmentioning

confidence: 99%

Alterations of Astrocytes in the Context of Schizophrenic Dementia

et al. 2020

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“…Neuropathology is evident at the molecular and neurotransmitter level within the ventral midbrain of people with schizophrenia ( 3 – 8 ), the region where the majority of dopamine cell bodies are found. Increases in pro-inflammatory cytokines and gliosis ( 9 ) are some of the most robust pathological changes found in the midbrain of people with schizophrenia to date; however, the inflammatory mechanisms of midbrain inflammation that may contribute to dopamine dysregulation in patients are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

“…A link between schizophrenia and the immune system is found using multiple strategies. Postmortem studies show increases in glial markers in the brain and higher expression of inflammatory mediators and cytokines in several brain areas, and increased inflammatory molecules are reported in the peripheral blood of people with schizophrenia ( 9 – 20 ). Importantly, the increases in cytokine transcripts are most obvious in a subset of schizophrenia cases, which we have termed a “high inflammatory biotype” or “high immune biotype” [e.g., ( 9 , 12 , 19 , 20 )].…”

Section: Introductionmentioning

confidence: 99%

“…Postmortem studies show increases in glial markers in the brain and higher expression of inflammatory mediators and cytokines in several brain areas, and increased inflammatory molecules are reported in the peripheral blood of people with schizophrenia ( 9 – 20 ). Importantly, the increases in cytokine transcripts are most obvious in a subset of schizophrenia cases, which we have termed a “high inflammatory biotype” or “high immune biotype” [e.g., ( 9 , 12 , 19 , 20 )]. High levels of inflammation are linked to more severe symptoms, greater neuropathology, and exacerbated cognitive deficits [e.g., ( 11 , 18 , 19 , 21 – 24 )].…”

Section: Introductionmentioning

confidence: 99%

“…High levels of inflammation are linked to more severe symptoms, greater neuropathology, and exacerbated cognitive deficits [e.g., ( 11 , 18 , 19 , 21 – 24 )]. Increased tissue inflammation can lead to increases in phagocytosis-primed macrophages in neurological disease and following brain injury ( 25 – 27 ); thus, we expect to find increased macrophages and higher complement production in the midbrain of those with schizophrenia, increased cytokines and gliosis ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

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Increased Macrophages and C1qA, C3, C4 Transcripts in the Midbrain of People With Schizophrenia

et al. 2020

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Increased cytokine and inflammatory-related transcripts are found in the ventral midbrain, a dopamine neuron-rich region associated with schizophrenia symptoms. In fact, half of schizophrenia cases can be defined as having a “high inflammatory/immune biotype.” Recent studies implicate both complement and macrophages in cortical neuroinflammation in schizophrenia. Our aim was to determine whether measures of transcripts related to phagocytosis/macrophages (CD163, CD64, and FN1), or related to macrophage adhesion [intercellular adhesion molecule 1 (ICAM1)], or whether CD163+ cell density, as well as protein and/or gene expression of complement pathway activators (C1qA) and mediators (C3 or C4), are increased in the midbrain in schizophrenia, especially in those with a high inflammatory biotype. We investigated whether complement mRNA levels correlate with macrophage and/or microglia and/or astrocyte markers. We found CD163+ cells around blood vessels and in the parenchyma and increases in ICAM1, CD163, CD64, and FN1 mRNAs as well as increases in all complement transcripts in the midbrain of schizophrenia cases with high inflammation. While we found positive correlations between complement transcripts (C1qA and C3) and microglia or astrocyte markers across diagnostic and inflammatory subgroups, the only unique strong positive correlation was between CD163 and C1qA mRNAs in schizophrenia cases with high inflammation. Our study is the first to suggest that more circulating macrophages may be attracted to the midbrain in schizophrenia, and that increased macrophages are linked to increased complement pathway activation in tissue and may contribute to dopamine dysregulation in schizophrenia. Single-cell transcriptomic studies and mechanistic preclinical studies are required to test these possibilities.

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Inflammation and Brain Structure in Schizophrenia and Other Neuropsychiatric Disorders

et al. 2022

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Key Points Question Is there evidence for a potential relationship between inflammation and brain structure, and is this relevant for schizophrenia and other neuropsychiatric disorders? Findings In this mendelian randomization study including 20 688 participants in the UK Biobank, genetically predicted levels of interleukin 6 were associated with gray matter volume and cortical thickness primarily in the middle temporal gyrus and superior frontal region. The middle temporal gyrus overexpressed a number of genes relevant to interleukin 6 pathway proteins and neuropsychiatric disorder ontologies, including schizophrenia and autism spectrum disorder. Meaning This study found that inflammation may be associated with brain structure and may be an early predeterminant of neuropsychiatric conditions, which has important implications for identification of risk and novel treatments.

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Increased levels of midbrain immune-related transcripts in schizophrenia and in murine offspring after maternal immune activation

Cited by 93 publications

References 70 publications

Alterations of Astrocytes in the Context of Schizophrenic Dementia

Alterations of Astrocytes in the Context of Schizophrenic Dementia

Increased Macrophages and C1qA, C3, C4 Transcripts in the Midbrain of People With Schizophrenia

Inflammation and Brain Structure in Schizophrenia and Other Neuropsychiatric Disorders

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