Developmental microglial priming in postmortem autism spectrum disorder temporal cortex
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Published on: October 17, 2025
Andrew S Lee1, Efrain C Azmitia2, Patricia M Whitaker-Azmitia3
1Department of Psychology, Stony Brook University, Stony Brook, NY 11794, USA; Department of Biology, New York University, New York, NY 10003, USA; Max Planck Institute for Biological Cybernetics, 72076 Tuebingen, Germany.
Abstract:
Microglia can shift into different complex morphologies depending on the microenvironment of the central nervous system (CNS). The distinct morphologies correlate with specific functions and can indicate the pathophysiological state of the CNS. Previous postmortem studies of autism spectrum disorder (ASD) showed neuroinflammation in ASD indicated by increased microglial density. These changes in the microglia density can be accompanied by changes in microglia phenotype but the individual contribution of different microglia phenotypes to the pathophysiology of ASD remains unclear. Here, we used an unbiased stereological approach to quantify six structurally and functionally distinct microglia phenotypes in postmortem human temporal cortex, which were immuno-stained with Iba1. The total density of all microglia phenotypes did not differ between ASD donors and typically developing individual donors. However, there was a significant decrease in ramified microglia in both gray matter and white matter of ASD, and a significant increase in primed microglia in gray matter of ASD compared to typically developing individuals. This increase in primed microglia showed a positive correlation with donor age in both gray matter and white of ASD, but not in typically developing individuals. Our results provide evidence of a shift in microglial phenotype that may indicate impaired synaptic plasticity and a chronic vulnerability to exaggerated immune responses.
Insights
In autism spectrum disorder (ASD), microglial phenotypes shift, with fewer ramified and more primed microglia observed. This suggests potential impaired synaptic plasticity and heightened immune responses in the brain.
Area of Science:
- Neuroscience
- Immunology
- Neurodevelopmental Disorders
Background:
- Microglia, the immune cells of the central nervous system (CNS), exhibit diverse morphologies linked to CNS function and pathology.
- Previous studies indicated increased microglial density in autism spectrum disorder (ASD), suggesting neuroinflammation, but specific phenotype contributions remain unclear.
Purpose of the Study:
- To quantify distinct microglia phenotypes in the temporal cortex of individuals with and without ASD.
- To investigate the relationship between microglial phenotypes and ASD pathophysiology.
Main Methods:
- Employed an unbiased stereological approach to analyze postmortem human temporal cortex samples.
- Immuno-stained tissue with Iba1 to identify and quantify six distinct microglia phenotypes.
Main Results:
- No significant difference in total microglia density was found between ASD and typically developing individuals.
- A significant decrease in ramified microglia and a significant increase in primed microglia were observed in the gray matter of ASD donors.
- Primed microglia density positively correlated with donor age in ASD individuals.
Conclusions:
- Findings suggest a shift in microglial phenotypes in ASD, characterized by reduced ramified and increased primed forms.
- This shift may indicate impaired synaptic plasticity and a predisposition to exaggerated immune responses in ASD.
- Microglia phenotype alterations, rather than density changes, may be more critical in ASD pathophysiology.
