Microglia activation in postmortem brains with schizophrenia demonstrates distinct morphological changes between
Ryan Gober1, Maryam Ardalan2,3, Seyedeh Marziyeh Jabbari Shiadeh2,3
1Brain Endowment Bank, University of Miami, Miami, FL, USA.
Abstract:
Schizophrenia (SCZ) is a psychiatric disorder that can include symptoms of disorganized speech and thoughts with uncertain underlying mechanisms possibly linked to over-activated microglia. In this study, we used brain samples from sixteen donors with SCZ and thirteen control donors to assess the differential activation of microglia by quantifying density and 3D reconstruction of microglia stained with ionized calcium-binding adaptor molecule-1 (Iba1). Our samples consisted of sections from the frontal, temporal, and cingulate cortical gray matter, subcortical white matter regions (SCWM), and included the anterior corpus callosum. In the first series of studies, we performed a density analysis followed by a spatial analysis to ascertain the microglial density, distribution, and soma size in SCZ brains. Second, we performed a series of morphological quantification techniques to investigate the arborization patterns of the microglia in SCZ. The results demonstrated an increase in microglia density in the cortical gray matter regions in SCZ cases, while in the SCWM, there was a significant increase in microglia density in the frontal and temporal, but not in the other brain regions of interest (ROIs). Spatial analysis using the "nearest neighbor" demonstrated that there was no effect in "clustering", but there were shorter distances between microglia seen in the SCZ cases. The morphological measures showed that there was a region-dependent increase in the microglia soma size in the SCZ cases while the Sholl analysis revealed a significant decrease in the microglia arborization in the SCZ cases across all the ROI's studied. An in-depth 3D reconstruction of microglia in Brodmann area 9 cortical region found that there was a significant association between age and reduced microglial arborization in the SCZ cases. This region-dependent age association can help determine whether longitudinal changes in microglial activation across age are brain region-dependent, which may point to potential therapeutic targets.
Insights
Microglia, immune cells in the brain, show increased density and altered morphology in schizophrenia (SCZ) patients. These changes, particularly reduced microglial arborization, may be age-dependent and offer potential therapeutic targets for SCZ.
Area of Science:
- Neuroscience
- Psychiatry
- Immunology
Background:
- Schizophrenia (SCZ) is a complex psychiatric disorder with poorly understood mechanisms.
- Over-activated microglia, the brain's immune cells, are a potential factor in SCZ pathogenesis.
- Understanding microglial changes in SCZ is crucial for identifying therapeutic targets.
Purpose of the Study:
- To investigate differential microglial activation in brain samples from SCZ patients and controls.
- To quantify microglial density, distribution, soma size, and arborization patterns in SCZ.
- To explore potential age-dependent alterations in microglial morphology in SCZ.
Main Methods:
- Analysis of brain tissue from 16 SCZ donors and 13 control donors.
- Quantification of microglial density, spatial distribution (nearest neighbor analysis), and soma size.
- 3D reconstruction and Sholl analysis to assess microglial arborization patterns in various brain regions.
Main Results:
- Increased microglia density observed in cortical gray matter and subcortical white matter (frontal, temporal) of SCZ brains.
- No significant change in microglial clustering, but shorter inter-microglial distances in SCZ.
- Region-dependent increase in microglia soma size and significant decrease in microglial arborization across all regions in SCZ cases.
- A significant association between age and reduced microglial arborization in Brodmann area 9 in SCZ.
Conclusions:
- Microglial activation is altered in SCZ, with increased density and reduced arborization.
- These microglial changes are region-dependent and may be associated with age in specific cortical areas.
- Findings suggest that region-dependent, age-associated microglial alterations could represent novel therapeutic targets for schizophrenia.
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