The immune system in autism: What does microglia have to do with it?

Microglia. Gerry Shaw / Wikimedia Commons

Much of the research on the postmortem autism brain has focused on neurons, the brain’s principal information processing cell. In the brain, however, there are other cells types, such as astrocytes and microglia, that could be involved in the autism spectrum disorder (ASD).

Astrocytes have multiple functions, including contributing to the protective barrier between the blood and the brain; microglia are the resident immune cells of the brain.

Microglia have enormous influence on brain development, as they regulate the number of neurons that are generated. In the mature brain, microglia mount the brain’s response to infection and clear the brain of debris after damage, such as a stroke. An early study revealed a marked increase in astrocyte and microglial activation in the brains of people with autism1 – a finding that was assumed to reflect a sustained inflammatory response.

Around the same time as this study was published, researchers were starting to recognize a new function of microglia to shape or “prune” brain cells2. Later, the crucial role of microglia in shaping cells, establishing connections and remodeling brain circuits was documented3. This indicates that microglia are not just responding to injury but are active participants in the development of brain connections. They help to set up the circuits of the brain by strengthening appropriate cell-to-cell connections and by eliminating improper connections in the brain. Since a popular hypothesis is that autism involves either too many or too few connections in the brain, it is no surprise that the role of microglia in autism has been under new interpretation.

Using resources from Autism BrainNet, researchers at both University of California Los Angeles (UCLA) and Johns Hopkins University examined how different types of genes are turned on or off4,5. Both studies discovered that as the activity of genes associated with microglia went up, the activity of genes associated with neuronal function went down. Based on their data, they concluded that in autism, the function of microglia was to regulate the plasticity of brain cells associated with autism. The fact that microglia were turned on in autism may be the result of all the activities required to reshape, mold and reconnect cells that started in irregular patterns. Recently, an immune receptor called TREM2, which has been shown to be critical for cutting down the excess of neurons during early brain development, has been found to be reduced in the brains of people with autism6. So, microglia’s role to ensure that the brain is connected properly may be a critical piece in understanding the neural mechanisms of autism.

Donna Werling, an investigator at the University of California at San Francisco (UCSF), has examined how gender may influence the activation of microglia. She and her colleagues have discovered that some genes associated with microglial activation are increased in neurotypical male brains, and others are increased in the brain of neurotypical females7. This is in contrast to autism genes, which are equally expressed in the brain of males and females with autism spectrum disorder (ASD). Some of these microglial genes may be turned on as the result of constantly reshaping and maintaining the autism brain. They may also be activated due to the presence of psychiatric comorbidities or the constant stress of having a neurodevelopmental condition. However, it seems they are not turned on because of a focal injury or toxicological process. Microglial activation represents the constant rewiring, reshaping, modeling, and restructuring of brain cells that are functioning differently in people with ASD7. Werling’s research shows that the different responses of microglia in male and female brains may contribute to our understanding of why more males are diagnosed compared to females.

References

1. Vargas D.L. et al. Ann. Neurol. 57, 67-81(2005) PubMed
2. Nimmerjahn A. et al. Science 308, 1314-1318 (2005) PubMed
3. Neale B.M. et al. Nature 485, 242-245 (2012) PubMed
4. Voineagu I. et al. Nature 474, 380-384 (2011) PubMed
5. Gupta S. et al. Nature 5, 5748 (2014) PubMed
6. Filipello F. et al. Immunity 48, 979-991 (2018) PubMed
7. Werling D.M. et al. Nat. Commun. 7, 10717 (2016) PubMed

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