Microglial activation and progressive brain changes in schizophrenia

Abstract

Schizophrenia is a debilitating disorder that typically begins in adolescence and is characterized by perceptual abnormalities, delusions, cognitive and behavioural disturbances and functional impairments. While current treatments can be effective, they are often insufficient to alleviate the full range of symptoms. Schizophrenia is associated with structural brain abnormalities including grey and white matter volume loss and impaired connectivity. Recent findings suggest these abnormalities follow a neuroprogressive course in the earliest stages of the illness, which may be associated with episodes of acute relapse. Neuroinflammation has been proposed as a potential mechanism underlying these brain changes, with evidence of increased density and activation of microglia, immune cells resident in the brain, at various stages of the illness. We review evidence for microglial dysfunction in schizophrenia from both neuroimaging and neuropathological data, with a specific focus on studies examining microglial activation in relation to the pathology of grey and white matter. The studies available indicate that the link between microglial dysfunction and brain change in schizophrenia remains an intriguing hypothesis worthy of further examination. Future studies in schizophrenia should: (i) use multimodal imaging to clarify this association by mapping brain changes longitudinally across illness stages in relation to microglial activation; (ii) clarify the nature of microglial dysfunction with markers specific to activation states and phenotypes; (iii) examine the role of microglia and neurons with reference to their overlapping roles in neuroinflammatory pathways; and (iv) examine the impact of novel immunomodulatory treatments on brain structure in schizophrenia. Linked Articles This article is part of a themed section on Inflammation: maladies, models, mechanisms and molecules. To view the other articles in this section visit 10.1111/bph.2016.173.issue-4

Positron Emission Tomography Studies of the Glial Cell Marker Translocator Protein in Patients With Psychosis: A Meta-analysis Using Individual Participant Data

“…Therefore, increases in numbers or activity of these cells in schizophrenia have been hypothesized (48,49). In postmortem studies, higher levels of brain glial cell markers, such as human leukocyte antigenantigen D related and CD11b, have been observed in patients, although results have been mixed (50)(51)(52). With regard to astrocyte markers, there is no evidence of any overall FC, frontal cortex; H0, null hypothesis; H1, hypothesis 1; H2, hypothesis 2; H0:H1, BF denoting evidence in favor of H0 over H1; H1:H0, BF denoting evidence in favor of H1 over H0; H0:H2, BF denoting evidence in favor of H0 over H2; H2:H0, BF denoting evidence in favor of H2 over H0; H1:H2, BF denoting evidence in favor of H1 over H2; H2:H1, BF denoting evidence in favor of H2 over H1; HIP, hippocampus; M1, Model 1; TC, temporal cortex; TSPO, translocator protein; V T , total distribution volume.…”

TSPO expression and brain structure in the psychosis spectrum

“…Supporting this evidence, studies on other neuropsychiatric disorders such as Alzheimer’s disease, Parkinson disease, acquired immunodeficiency syndrome, multiple sclerosis and prion related disease have all shown co-localization of TSPO density and neurodegenerative alterations in the brain 27 . More recently some studies suggested a link between inflammation (in the periphery) and gray matter deficits in psychosis risk 28 . In individuals at clinical high risk (CHR) for psychosis who converted to psychosis, the gray matter loss in the frontal lobe was associated with the baseline levels of proinflammatory cytokines in plasma 29 .…”

Vitamin-D Deficiency As a Potential Environmental Risk Factor in Multiple Sclerosis, Schizophrenia, and Autism

“…Their activation interferes with neuronal survival by increasing oxidative stress and decreasing neurotropic support and has been linked to MS (43), schizophrenia (44, 45), and autism (46). As microglia cells play a pivotal role in neuroinflammation and neurodegeneration, downregulation of their pro-inflammatory cytokine production and release of free radicals by vitamin-D may be neuroprotective (47).…”