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

Morgan, John T.; Chana, Gursharan; Pardo, Carlos A.; Achim, Cristian L.; Semendeferi, Katerina; Buckwalter, J. A.; Courchesne, Eric; Everall, Ian

doi:10.1016/j.biopsych.2010.05.024

Cited by 603 publications

(496 citation statements)

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“…Synaptic deficits are a hallmark of various neurodevelopmental brain disorders, including schizophrenia and autism (reviewed in Eastwood, 2004;Ebrahimi--Fakhari and Sahin, 2015;Harrison, 2004). These disorders have also been associated with altered microglia functions and associated neuroinflammatory changes (Arion et al, 2007;Doorduin et al, 2009;Fung et al, 2014;Morgan et al, 2010;Tetreault et al, 2012;van Berckel et al, 2008;Volk et al, 2015). It remains elusive, however, whether and to what extent such microglial abnormalities may be responsible for the development of synaptic deficits as, for example, seen in schizophrenia or autism Onore et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Even though the underlying mechanisms and functional role of increased hippocampal IL--1β expression remains to be examined in our model, our data clearly demonstrate that abnormal pro--inflammatory cytokine expression in the brain can occur without concomitant microglia abnormalities. These findings may also have important implications for the current attempts to define "neuroinflammation" in neurodevelopmental disorders such as schizophrenia and autism, especially for those that rely on the examination of microglia only (Doorduin et al, 2009;Kenk et al, 2015;Morgan et al, 2010;Pasternak et al, 2015;Tetreault et al, 2012;van Berckel et al, 2008).…”

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confidence: 98%

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Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies

Giovanoli

Weber‐Stadlbauer

Schedlowski

et al. 2016

Brain, Behavior, and Immunity

119

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Prenatal exposure to infectious or inflammatory insults can increase the risk of developing neuropsychiatric disorder in later life, including schizophrenia, bipolar disorder, and autism. These brain disorders are also characterized by pre-and postsynaptic deficits. Using a well-established mouse model of maternal exposure to the viral mimetic polyriboinosinic-polyribocytidilic acid [poly(I:C)], we examined whether prenatal immune activation might cause synaptic deficits in the hippocampal formation of pubescent and adult offspring. Based on the widely appreciated role of microglia in synaptic pruning, we further explored possible associations between synaptic deficits and microglia anomalies in offspring of poly(I:C)-exposed and control mothers. We found that prenatal immune activation induced an adult onset of presynaptic hippocampal deficits (as evaluated by synaptophysin and bassoon density). The early-life insult further caused postsynaptic hippocampal deficits in pubescence (as evaluated by PSD95 and SynGAP density), some of which persisted into adulthood. In contrast, prenatal immune activation did not change microglia (or astrocyte) density, nor did it alter their activation phenotypes. The prenatal manipulation did also not cause signs of persistent systemic inflammation. Despite the absence of overt glial anomalies or systemic inflammation, adult offspring exposed to prenatal immune activation displayed increased hippocampal IL-1 levels. Taken together, our findings demonstrate that age-dependent synaptic deficits and abnormal pro-inflammatory cytokine expression can occur during postnatal brain maturation in the absence of microglial anomalies or systemic inflammation. AbstractPrenatal exposure to infectious or inflammatory insults can increase the risk of developing neuropsychiatric disorder in later life, including schizophrenia, bipolar disorder, and autism. These brain disorders are also characterized by pre--and postsynaptic deficits.Using a well--established mouse model of maternal exposure to the viral mimetic polyriboinosinic--polyribocytidilic acid [poly(I:C)], we examined whether prenatal immune activation might cause synaptic deficits in the hippocampal formation of pubescent and adult offspring. Based on the widely appreciated role of microglia in synaptic pruning, we further explored possible associations between synaptic deficits and microglia anomalies in offspring of poly(I:C)--exposed and control mothers. We found that prenatal immune activation induced adult onset of presynaptic hippocampal deficits (as evaluated by synaptophysin and bassoon density). The early--life insult further caused postsynaptic hippocampal deficits in pubescence (as evaluated by PSD95 and SynGAP density), some of which persisted into adulthood. In contrast, prenatal immune activation did not change microglia (or astrocyte) density, nor did it alter their activation phenotypes. The prenatal manipulation did also not cause signs of persistent systemic inflammation. Despite the absence of overt glial a...

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 98%

Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies

Giovanoli

Weber‐Stadlbauer

Schedlowski

et al. 2016

Brain, Behavior, and Immunity

119

View full text Add to dashboard Cite

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“…Injections of IgG collected from mothers of children with ASD into pregnant rhesus monkeys during the first and second trimesters led to altered brain volume and social behavior development in the offspring [75]. Analyses of post-mortem brain tissues of ASD patients with ages ranging from children to adults have revealed microglia activation and increased cytokines including TNF-α and IL-6, suggesting ongoing neuroinflammation in the brains of ASD patients [76,77]. These findings indicate that immune responses may impact on ASD pathogenesis.…”

Section: Immune Dysregulation In Asdmentioning

confidence: 99%

“…They can secrete TNF-α and IL-6 under inflammatory conditions, provide growth factors in early synaptogenesis, eliminate redundant synapses, and modulate synaptic transmission [78,79]. Morgan et al found microglial cells were activated in approximately 40% of their autism samples together with an increase in the average microglial somal volume in white mater [77]. Suzuki et al further investigated the patterns of distribution of microglial activation in the brain of ASD patients by PET imaging, and found increased microglial activation in the dorsolateral prefrontal cortex in ASD patients although the microglial distribution patterns were similar [80].…”

Section: Immune Dysregulation In Asdmentioning

confidence: 99%

Genetic architecture, epigenetic influence and environment exposure in the pathogenesis of Autism

2015

Sci. China Life Sci.

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Autism spectrum disorder (ASD) is a spectral neurodevelopment disorder affecting approximately 1% of the population. ASD is characterized by impairments in reciprocal social interaction, communication deficits and restricted patterns of behavior. Multiple factors, including genetic/genomic, epigenetic/epigenomic and environmental, are thought to be necessary for autism development. Recent reviews have provided further insight into the genetic/genomic basis of ASD. It has long been suspected that epigenetic mechanisms, including DNA methylation, chromatin structures and long non-coding RNAs may play important roles in the pathology of ASD. In addition to genetic/genomic alterations and epigenetic/epigenomic influences, environmental exposures have been widely accepted as an important role in autism etiology, among which immune dysregulation and gastrointestinal microbiota are two prominent ones. autism spectrum disorder, genetic architecture, genomic disorder, gene mutation, copy number variants, single nucleotide variants, genetic pathways, epigenetic influence, DNA methylation, chromatin remodeling, long non-coding RNAs, environment exposure, immune dysregulation, gastrointestinal microbiota Citation:Yu L, Wu YM, Wu BL. Genetic architecture, epigenetic influence and environment exposure in the pathogenesis of Autism. Sci China Life Sci, 2015, 58: 958-967,

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“…Several studies report striking immune dysregulation in the neural, peripheral and enteric immune systems, of autistic individuals (Figure 1). Postmortem brains from ASD patients exhibit elevated activation of microglia and astrocytes, in addition to increased levels of pro-inflammatory cytokines [81,82]. Notably, transcriptome analysis of ASD brains reveals altered expression of neuronal-related genes, including ASD susceptibility genes, alongside dysregulated expression of immune-related genes related to inflammation and glial activation [79,83].…”

Section: Immune Dysregulation In Asdmentioning

confidence: 99%

Immune Involvement in Autism Spectrum Disorder as a Basis for Animal Models

Hsiao¹

2012

Autism

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Several of the environmental stimuli suggested to play a role in the pathogenesis of ASD involve altered immune responses during gestation. In this review, we discuss maternal immune activation as a primary risk factor for ASD, with an emphasis on recent findings from animal models of prenatal immune challenges. We further address the presence of autoantibodies as an additional immune-related autism risk factor, drawing upon work done in rodent and monkey models. We then explore the intersection between genetic and environmental susceptibility, with a focus on gene-environment interactions and immune involvement, in genetic risk factors for autism. Finally, we provide emerging evidence for the role of immune dysregulation in the pathogenesis of ASD.

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

Cited by 603 publications

References 64 publications

Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies

Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies

Genetic architecture, epigenetic influence and environment exposure in the pathogenesis of Autism

Immune Involvement in Autism Spectrum Disorder as a Basis for Animal Models

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