Abstract
Schizophrenia is a psychiatric disorder which has a lifetime prevalence of ~1%. Multiple candidate mechanisms have been proposed in the pathogenesis of schizophrenia. One such mechanism is the involvement of neuroinflammation. Clinical studies, including neuroimaging, peripheral biomarkers and randomized control trials, have suggested the presence of neuroinflammation in schizophrenia. Many studies have also measured markers of neuroinflammation in postmortem brain samples from schizophrenia patients. The objective of this study was to conduct a systematic search of the literature on neuroinflammation in postmortem brains of schizophrenia patients indexed in MEDLINE, Embase and PsycINFO. Databases were searched up until 20th March 2016 for articles published on postmortem brains in schizophrenia evaluating microglia, astrocytes, glia, cytokines, the arachidonic cascade, substance P and other markers of neuroinflammation. Two independent reviewers extracted the data. Out of 5385 articles yielded by the search, 119 articles were identified that measured neuroinflammatory markers in schizophrenic postmortem brains. Glial fibrillary acidic protein expression was elevated, lower or unchanged in 6, 6 and 21 studies, respectively, and similar results were obtained for glial cell densities. On the other hand, microglial markers were increased, lower or unchanged in schizophrenia in 11, 3 and 8 studies, respectively. Results were variable across all other markers, but SERPINA3 and IFITM were consistently increased in 4 and 5 studies, respectively. Despite the variability, some studies evaluating neuroinflammation in postmortem brains in schizophrenia suggest an increase in microglial activity and other markers such as SERPINA3 and IFITM. Variability across studies is partially explained by multiple factors including brain region evaluated, source of the brain, diagnosis, age at time of death, age of onset and the presence of suicide victims in the cohort.
Highlights
Schizophrenia is a psychiatric disorder which affects ~ 0.5 to 1% of the population in their lifetime.[1,2] Psychosis normally arises in the late teenage years or early adulthood, between 18 and 25 years of age.[3]
Following injury or the exposure to pro-inflammatory signals such as interferon (IFN)-γ and tumor necrosis factor (TNF)-α, ramified microglia can become activated and release pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, IFN-γ or chemokine (c-x-c motif) ligand (CCL) 11.13 Microglia increase the expression of cyclooxygenase (COX)-2, an enzyme involved in the arachidonic cascade, which can lead to the production of the pro-inflammatory lipid mediator prostaglandin E2.14 Pro-inflammatory cytokines released from microglia, such as IL-1β, can activate astrocytes
In a study of 19 schizophrenics, TNF-α receptor 1 mRNA was increased in the dorsolateral prefrontal and cingulate cortices compared to controls, whereas soluble TNF-α protein, transmembrane TNF-α protein and TNF-α receptor 2 mRNA concentrations were unchanged.[138]
Summary
Schizophrenia is a psychiatric disorder which affects ~ 0.5 to 1% of the population in their lifetime.[1,2] Psychosis normally arises in the late teenage years or early adulthood, between 18 and 25 years of age.[3] the cause underlying this mental illness remains to be elucidated, several biological factors have been proposed, including abnormalities in oligodendrocytes,[4,5] N-methyl-D-aspartate (NMDA) signaling[6] and dopaminergic transmission.[7]. Neuroinflammation has been suggested to be a potential contributor in the pathogenesis of the schizophrenia.[8,9,10,11] Classically, the brain is considered to be immunologically privileged due to the blood–brain barrier limiting cell entry.[12] Under normal conditions, microglia, the resident immune cells of the brain, are found in a ramified (‘resting’) state, surveying the environment. Activated astrocytes have the ability to release pro-inflammatory cytokines and chemokines, such as IL-1β, CCL5 and TNF-α,15 and typically display increased glial fibrillary acidic protein (GFAP) expression.[16]
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