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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 indicate the pathophysiological state of the CNS. Previous postmortem studies of autism spectrum disorder (ASD) showed regions of neuroinflammation in ASD resulting in changes in microglia number. These change 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 semi-stereological approach to quantify six structurally and functionally distinct microglia phenotypes in postmortem human temporal cortex, which were immuno-stained with an antibody against Iba1. In addition to stereological measures, we used three different methods to quantify Iba1-immunoreactive microglia. We now report in human postmortem cortex measures on six distinct phenotypes including ramified, primed, reactive, amoeboid, rod and dystrophic. The total density of all microglia phenotypes did not differ between ASD donors (n=10, 14.6 yrs, range 2.8-29 yrs) and typically developing individual donors (controls, n=9, 14.9 yrs, 1.8-32 yrs). 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 controls. This increase in primed microglia showed a positive correlation with donor age in both gray matter and white of ASD, but not in controls. Our results provide evidence of a shift in microglial phenotype that may indicate impaired synaptic plasticity, and a chronic vulnerability to exaggerated immune responses. We suggest the priming of microglia is most likely due to the disruption of maternal environment during pregnancy and developmental influences rather than genetic predispositions, but the exact mechanism is unclear. Further investigation in the underlying mechanism of the shift in microglia phenotype may be a step forward in understanding the significance of maternal environment and microglial pathology in ASD. Quantitative methods of measuring Iba1-immunoreactive microglia did not show significant difference between ASD and controls, which suggests the importance of using visual categorization or finer and/or more sensitive methods when neuroinflammation is subtle to delineate the complex morphology of microglia.
