Elsevier

Biological Psychiatry

Volume 68, Issue 4, 15 August 2010, Pages 368-376
Biological Psychiatry

Archival Report
Microglial Activation and Increased Microglial Density Observed in the Dorsolateral Prefrontal Cortex in Autism

https://doi.org/10.1016/j.biopsych.2010.05.024Get rights and content

Background

In the neurodevelopmental disorder autism, several neuroimmune abnormalities have been reported. However, it is unknown whether microglial somal volume or density are altered in the cortex and whether any alteration is associated with age or other potential covariates.

Methods

Microglia in sections from the dorsolateral prefrontal cortex of nonmacrencephalic male cases with autism (n = 13) and control cases (n = 9) were visualized via ionized calcium binding adapter molecule 1 immunohistochemistry. In addition to a neuropathological assessment, microglial cell density was stereologically estimated via optical fractionator and average somal volume was quantified via isotropic nucleator.

Results

Microglia appeared markedly activated in 5 of 13 cases with autism, including 2 of 3 under age 6, and marginally activated in an additional 4 of 13 cases. Morphological alterations included somal enlargement, process retraction and thickening, and extension of filopodia from processes. Average microglial somal volume was significantly increased in white matter (p = .013), with a trend in gray matter (p = .098). Microglial cell density was increased in gray matter (p = .002). Seizure history did not influence any activation measure.

Conclusions

The activation profile described represents a neuropathological alteration in a sizeable fraction of cases with autism. Given its early presence, microglial activation may play a central role in the pathogenesis of autism in a substantial proportion of patients. Alternatively, activation may represent a response of the innate neuroimmune system to synaptic, neuronal, or neuronal network disturbances, or reflect genetic and/or environmental abnormalities impacting multiple cellular populations.

Section snippets

Tissue Acquisition

Fifteen autism cases and 9 control cases were examined (Table 1). Two of the autism cases, a young female and a severely macrencephalic male, were segregated from the quantitative assessment group a priori. The quantitative assessment autism group was comprised of all male cases with suitable formalin-fixed dlPFC tissue available from the national brain banks and the Courchesne laboratory collection. Twelve of the 15 autism cases were diagnosed with autism via the Autism Diagnostic

Results

Microglial cell morphology was strongly altered (++) in 3 of 13 autism cases (Figure 1). Moderate alterations (+) were observed in 2 autism cases, both of which were under 6 years of age. Minor alterations (0/+) were observed in an additional 4 of 13 autism cases and 1 of 9 control cases; some of these alterations may reflect modest perimortem morphological changes. The alterations extended from the pial surface to deep white matter and were primarily characterized by somal enlargement and loss

Discussion

Moderate to strong alterations in Iba-1 positive microglial morphology indicative of activation (13, 29) are present in 5 of 13 postmortem cases with autism, and mild alterations are present in an additional 4 of 13 cases. These alterations are reflected in a significant increase in average microglial somal volume in white matter and microglial density in gray matter, as well as a trend in microglial somal volume in gray matter. These observations appear to reflect a relatively frequent

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    Authors EC and IPE contributed equally to this work.

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