Quantitative Evaluation of Microglial Activation and Vascularization in Suicide

Accumulated evidence points to immunological factors in psychiatric disorders. In a variety of chronic neurological disorders, exacerbation is associated with inflammation and a loss of integrity of the blood-brain barrier. Microglia, the principal brain immunological cells in the healthy state, respond to changes in the internal environment of the brain through a sequence of activated states. This study compared microglial phenotypes in the white matter of autopsy brains from 11 suicide victims and 25 subjects who died involuntarily. Both groups included cases with and without major psychiatric disorders, which were determined by PA interviews. Cases were matched for sex, age, and as closely as possible, for psychiatric diagnosis. Two serial 6-µm paraffin sections from each of 5-10 blocks comprising an entire coronal section of the left frontal lobe at the level of the tip of the anterior horn of the lateral ventricle were stained with peroxidase double labeling for Iba-1, labeling all microglia, and CD68, whose staining increases in activated microglia. Densities of macrophages and resting, activated, and intra- or perivascular microglia in ventral, dorsal, medial and lateral prefrontal white matter were estimated with a physical disector. To examine changes in the blood-brain barrier, vessel length density was evaluated in prefrontal grey and white matter using peroxidase staining for an adhesion molecule marker CD31. To determine lifetime aggression scores of the deceased, PA included the Brown-Goodwin Aggression Scale questionnaire. Based on the lifetime aggression score, subjects were subdivided into low and high aggression groups, and the relationship between aggression, manner of death and microglial activation was investigated. We found no statistically significant effects of diagnosis. In comparison with subjects who did not die by suicide, suicide victims had a significantly higher density of microglial cells within or in contact with blood vessel walls in dorsal white matter. In addition, within-subject analysis showed a significantly increased density of activated microglia in ventral relative to dorsal white matter of suicide victims. No significant effects on vessel length density were detected. Perivascular cell density was significantly increased in aggressive subjects in whole, medial, and ventral white matter. Total cell densities were increased in the same regions if aggressive subjects died by suicide. Changes in microglial activity may precede or follow a disruption in the blood-brain barrier, leading to an influx of peripheral inflammatory molecules and loss of white matter integrity. Increased microglial activation in ventral white matter may be related to a shift in tryptophan synthesis, decrease in 5-HT neurotransmission, and a hyper-excitatory state of neurons in or projecting to adjacent cortex. Distinct regional patterns of perivascular infiltration associated with completed suicide and aggression suggest that in addition to a disruption in fronto-limbic connectivity, suicide victims may have a ventral-dorsal dissociation. Further studies are needed to investigate whether suicide is associated with changes in specific phenotypes of perivascular microglia and whether the blood-brain barrier is compromised

A loss of mature microglial markers without immune activation in schizophrenia

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