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

4 Aug

Here is a study that will likely be discussed for a long time to come. There has been a lot of interest in the study by John’s Hopkins researchers (Pardo, et al.) on microglial activity in the brains of autopsied autistics. A paper just released by Prof. Pardo together with Prof. Courchesne at UCSD shows markedly increased microglial cell activiation in 5 of 13 autistics, including children under 6.

The exact implications of this are not yet determined. The authors conclude the abstract with

“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.”

Here is the full abstract:

Biol Psychiatry. 2010 Aug 15;68(4):368-376.
Microglial Activation and Increased Microglial Density Observed in the Dorsolateral Prefrontal Cortex in Autism.

Morgan JT, Chana G, Pardo CA, Achim C, Semendeferi K, Buckwalter J, Courchesne E, Everall IP.

Department of Neuroscience, School of Medicine, University of California, San Diego, La Jolla, California.
Abstract

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. Copyright © 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

PMID: 20674603 [PubMed – as supplied by publisher]

4 Responses to “Microglial Activation and Increased Microglial Density Observed in the Dorsolateral Prefrontal Cortex in Autism.”

  1. passionlessDrone August 4, 2010 at 15:21 #

    Hi Sullivan –

    This is a neat paper, but not as thorough as the last microglia activation paper from some of the same authors.

    Reading this, it occurs to me that we may have animal models that can explain some of what was observed. Specifically, Morgan observed an increased number of microglia in the autism cases.

    In Enduring consequences of early-life infection on glial and neural cell genesis within cognitive regions of the brain

    researchers reported an increased number of microglia in some areas of rodents infected with e-coli neonatally.

    Systemic infection with Escherichia coli on postnatal day (P) 4 in rats results in significantly altered brain cytokine responses and behavioral changes in adulthood, but only in response to a subsequent immune challenge with lipopolysaccharide [LPS]. The basis for these changes may be long-term changes in glial cell function. We assessed glial and neural cell genesis in the hippocampus, parietal cortex (PAR), and prefrontal cortex (PFC), in neonates just after the infection, as well as in adulthood in response to LPS. E. coli increased the number of newborn microglia within the hippocampus and PAR compared to controls. The total number of microglia was also significantly increased in E. coli-treated pups, with a concomitant decrease in total proliferation. On P33, there were large decreases in numbers of cells coexpressing BrdU and NeuN in all brain regions of E. coli rats compared to controls. In adulthood, basal neurogenesis within the dentate gyrus (DG) did not differ between groups; however, in response to LPS, there was a decrease in neurogenesis in early-infected rats, but an increase in controls to the same challenge. There were also significantly more microglia in the adult DG of early-infected rats, although microglial proliferation in response to LPS was increased in controls. Taken together, we have provided evidence that systemic infection with E. coli early in life has significant, enduring consequences for brain development and subsequent adult function. These changes include marked alterations in glia, as well as influences on neurogenesis in brain regions important for cognition.

    The jump from rodent to human is complex, but this model does seem to fit nicely with what is proposed involving maternal infection and subsequent brain development.

    Also of particular interest to my mind in this paper is that they seem to be making progress in describing the neuroinflammation; or at least trying to see if it matches existing patterns, something I haven’t seen it tested for as such previously.

    Second, there is no increase in microglial
    colocalization with a receptor, IL-1R1, typically upregulated in
    acute inflammatory reactions (28). The trend toward an increase
    in colocalization in control cases may also hint at downregulation
    of inflammatory signal receptors in a chronically activated system

    – pD

  2. RAJ August 5, 2010 at 13:39 #

    Microglial activation in neurogical disorders is not new. It has been observed in Alzheimer’s disease, epilepsy, schizophrenia and mental retardation. Giving the overlapping co-occurence between mental retardation, epilepsy and autism it would be interesting to see the IQ scores of the particpants.

    Autism researchers seem to be unable to solve the intractable problem of non-specific findings in autism.

    http://www.ncbi.nlm.nih.gov/pubmed/20577641

    http://www.ncbi.nlm.nih.gov/pubmed/20109113

    http://www.ncbi.nlm.nih.gov/pubmed/20021679

    So what is this study telling us. There are structural anomolies in the brain in autism but the anomolies are not specific to autism.

  3. dr treg August 6, 2010 at 07:49 #

    It is unfortunate that they didnt measure regulatory T cells numbers/activity. TREGS are important in the control of microglial activity. I am awaiting the results of Assistant Professor DeWitt`s study of TREGS in autism.
    http://www.ecu.edu/cs-dhs/pharmacology/DeWitt09.cfm

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