Neuroinflammation in the dorsolateral prefrontal cortex in elderly chronic schizophrenia

López‐González, Irene; Pinacho, Raquel; Vila, Èlia; Escanilla, Ana; Ferrer, Isidre; Ramos, Belén

doi:10.1016/j.euroneuro.2018.12.011

Cited by 38 publications

(29 citation statements)

References 76 publications

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“…Thus, our analysis suggested the role of IL-10 as an endogenous regulator of the KP in PFC and CB, although at a different level. Decreased protein and mRNA expression of IL-10 in SZ has been also reported previously at mRNA level in PFC, as well as no differences in IL-1β, as in our experimental conditions [21, 30].…”

Section: Discussionsupporting

confidence: 89%

“…Differences in the protein expression levels of the downstream member between the group with samples with the highest protein levels and that with the lowest protein levels were evaluated. Significant correlations in this co-expression analysis indicate that the interaction distance between these two proteins is short in this network [30]. The pathway was “coupled” when all the downstream members of the pathway correlate with the upstream member, reflecting the proximity of the members in the pathway.…”

Section: Methodsmentioning

confidence: 99%

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Kynurenine pathway in post-mortem prefrontal cortex and cerebellum in schizophrenia: relationship with monoamines and symptomatology

Afia

Vila

MacDowell

et al. 2021

Preprint

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Background: the cortico-cerebellar-thalamic-cortical circuit has been implicated in the emergence of psychotic symptoms in schizophrenia (SZ). The kynurenine pathway (KP) has been linked to alterations in glutamatergic and monoaminergic neurotransmission and to SZ symptomatology through the production of the metabolites quinolinic acid (QA) and kynurenic acid (KYNA). Methods: this work describes alterations in KP in the post-mortem prefrontal cortex (PFC) and cerebellum (CB) of 15 chronic SZ patients and 14 control subjects in PFC and 13 control subjects in CB using immunoblot for protein levels and ELISA for interleukins and QA and KYNA determinations. Monoamine metabolites were analysed by High Performance Liquid Chromatography and SZ symptomatology was assessed by Positive and Negative Syndrome Scale (PANSS). The association of KP with inflammatory mediators, monoamine metabolism and SZ symptomatology was explored. Results: in the PFC, the presence of the anti-inflammatory cytokine IL-10 together with IDO2 and KATII enzymes decreased in SZ, while TDO and KMO enzymes expression increased. A network interaction analysis showed that in the PFC IL-10 was coupled to the QA branch of the kynurenine pathway (TDO-KMO-QA), whereas IL-10 associated with KMO in CB. KYNA in the CB inversely correlated with negative and general PANSS psychopathology. Although there were no changes in monoamine metabolites content in the PFC in SZ, a network interaction analysis showed associations between dopamine and methoxyhydroxyphenylglycol degradation metabolite. Direct correlations were found between general PANSS psychopathology and the serotonin degradation metabolite, 5-hydroxyindoleacetic acid. Interestingly, KYNA in the CB inversely correlated with 5-hydroxyindoleacetic acid in the PFC. Conclusions: thus, this work found alterations in KP in two brain areas belonging to the cortico-cerebellar-thalamic-cortical circuit associated with SZ symptomatology, with a possible impact across areas in 5-HT degradation.

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Section: Discussionsupporting

confidence: 89%

Section: Methodsmentioning

confidence: 99%

Kynurenine pathway in post-mortem prefrontal cortex and cerebellum in schizophrenia: relationship with monoamines and symptomatology

Afia

Vila

MacDowell

et al. 2021

Preprint

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“…Besides, area of nucleus of microglial cells was correlated negatively significantly with age in the SPPS subgroup. Neuroinflammation has recently been reported in the PFC in elderly chronic schizophrenia patients (88). Taken together, these data suggest that microglia is involved in a progressive course of schizophrenia.…”

Section: Discussionmentioning

confidence: 54%

Dystrophy of Oligodendrocytes and Adjacent Microglia in Prefrontal Gray Matter in Schizophrenia

et al. 2020

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Background: Some evidence support the notion that microglia activation in acute state of schizophrenia might contribute to damage of oligodendrocytes and myelinated fibers. Previously we found dystrophic changes of oligodendrocytes in prefrontal white matter in schizophrenia subjects displaying predominantly positive symptoms as compared to controls. The aim of the study was to verify whether microglial activation might contribute to dystrophic changes of oligodendrocytes in prefrontal gray matter in this clinical subgroup. Methods: Transmission electron microscopy and morphometry of microglia and adjacent oligodendrocytes were performed in layer 5 of the prefrontal cortex (BA10) in the schizophrenia subjects displaying predominantly positive symptoms (SPPS, n = 12), predominantly negative symptoms (SPNS, n = 9) and healthy controls (n = 20). Results: Qualitative study showed microglial activation and dystrophic alterations of microglia and oligodendrocytes adjacent to each other in both subgroups as compared to controls. A significant reduction in volume density (Vv) and the number (N) of mitochondria and an increase in N of lipofuscin granules were found in oligodendrocytes and adjacent microglia in both subgroups. Vv of lipofuscin granules, Vv and N of vacuoles of endoplasmic reticulum in microglia were increased significantly in the SPPS subgroup as compared to controls. In the SPPS subgroup Vv and N of mitochondria in microglia were correlated with N of vacuoles in microglia (r =-0.61, p < 0.05) and with Vv (r = 0.79, p < 0.01) and N (r = 0.59, p < 0.05) of mitochondria in oligodendrocytes. Vv of mitochondria in microglia was also correlated with Vv and N of vacuoles in oligodendrocytes in the SPPS subgroup (r = 0.76, p < 0.01). Area of nucleus of microglial cells was correlated negatively with age (r =-0.76, p < 0.01) and age at illness onset (r =-0.65, p < 0.05) in the SPPS subgroup. In the SPNS subgroup N of mitochondria in microglia was correlated with Vv of lipofuscin granules in oligodendrocytes (r =-0.9, p < 0.01). There were no significant correlations between these parameters in the control group. Discussion: Microglial dystrophy might contribute to oligodendrocyte dystrophy in the schizophrenia subjects with predominantly positive symptoms during relapse. Mitochondria in microglia and oligodendrocytes may be a target for treatment strategy of schizophrenia.

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“…Previous reviews by Trepanier and Van Kesteren reported evidence for an increased microglial density in SCZ (Trépanier et al, 2016; Van Kesteren et al, 2017). Here, we included 10 additional studies (Brisch et al, 2017; Durrenberger et al, 2015; Fiorentino et al, 2016; López‐González et al, 2019; Nakatani et al, 2006; Petrasch‐Parwez et al, 2020; Schmitt et al, 2011; Schnieder et al, 2014; Seredenina et al, 2017; Sinkus, Adams, Logel, Freedman, & Leonard, 2013) and excluded two studies with overlapping samples (Gos et al, 2014; Steiner et al, 2008), as well as one study that had a strong effect in the previous reviews (ES: 1.79 95% CI 0.76–2.83), but was retracted because of data falsification (Rao, Kim, Harry, Rapoport, & Reese, 2013). In addition, we applied a nesting approach on studies including multiple brain regions.…”

Section: Discussionmentioning

confidence: 99%

A loss of mature microglial markers without immune activation in schizophrenia

Snijders

Zuiden

Sneeboer³

et al. 2021

Glia

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Microglia, the immune cells of the brain, are important for neurodevelopment and have been hypothesized to play a role in the pathogenesis of schizophrenia (SCZ). Although previous postmortem studies pointed toward presence of microglial activation, this view has been challenged by more recent hypothesis‐driven and hypothesis‐free analyses. The aim of the present study is to further understand the observed microglial changes in SCZ. We first performed a detailed meta‐analysis on studies that analyzed microglial cell density, microglial morphology, and expression of microglial‐specific markers. We then further explored findings from the temporal cortex by performing immunostainings and qPCRs on an additional dataset. A random effect meta‐analysis showed that the density of microglial cells was unaltered in SCZ (ES: 0.144 95% CI: 0.102 to 0.390, p = .250), and clear changes in microglial morphology were also absent. The expression of several microglial specific genes, such as CX3CR1, CSF1R, IRF8, OLR1, and TMEM119 was decreased in SCZ (ES: −0.417 95% CI: −0.417 to −0.546, p < .0001), consistent with genome‐wide transcriptome meta‐analysis results. These results indicate a change in microglial phenotype rather than density, which was validated with the use of TMEM119/Iba1 immunostainings on temporal cortex of a separate cohort. Changes in microglial gene expression were overlapping between SCZ and other psychiatric disorders, but largely opposite from changes reported in Alzheimer's disease. This distinct microglial phenotype provides a crucial molecular hallmark for future research into the role of microglia in SCZ and other psychiatric disorders.

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Neuroinflammation in the dorsolateral prefrontal cortex in elderly chronic schizophrenia

Abstract: Cognitive deterioration and symptom progression occur in schizophrenia over the course of the disorder. A dysfunction of the immune system/neuroinflammatory pathways has been linked to schizophrenia (SZ). These altered processes in the dorsolateral prefrontal cortex (DLPFC)

Cited by 38 publications

References 76 publications

Kynurenine pathway in post-mortem prefrontal cortex and cerebellum in schizophrenia: relationship with monoamines and symptomatology

Kynurenine pathway in post-mortem prefrontal cortex and cerebellum in schizophrenia: relationship with monoamines and symptomatology

Dystrophy of Oligodendrocytes and Adjacent Microglia in Prefrontal Gray Matter in Schizophrenia

A loss of mature microglial markers without immune activation in schizophrenia

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