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Opinion / Viewpoint

Brain’s immune cells show intriguing links to autism

by  /  13 August 2013
The Expert:
Expert

Beth Stevens

Assistant Professor, Harvard University

Synaptic snippers: The brain’s immune molecules may support normal brain development by pruning inappropriate neuronal connections.

Immune cells that reside in the brain, called microglia, defend the brain against biological threats and injury. Emerging evidence indicates that microglia are altered in some individuals with autism, raising questions about their potential role in brain development.

When challenged, these chameleon-like cells transform from a resting to an activated, or macrophage-like, state and are rapidly recruited to sites of damage. There, they engulf debris as well as unwanted and dying cells. At the same time, they contribute to brain inflammation by releasing immune proteins called cytokines and other proteins that may be toxic to the brain1, 2.

Microglia activation is a hallmark of Alzheimer ’s disease and other adult-onset neurodegenerative diseases. However, several postmortem studies have revealed that activated microglia are also elevated in the brains of young individuals with autism, despite the absence of neurodegeneration or other obvious harm to the brain3.

Intriguingly, a positron emission tomography imaging study published in January — using a radioactive tracer that binds to activated microglia — revealed an elevated number of activated microglia in autism-linked brain regions (including the cerebellum) in people with the disorder. Microglia may thus function as a potential biomarker for at-risk brain regions in autism.

Although the potential link between microglia and autism is intriguing, it is not yet clear what changes in microglia activation tell us about autism. Are microglia simply responding to changes in the brain environment? Or could they play an active or even causal role in autism?

These key questions have been challenging to parse, in part because we know surprisingly little about the normal function of microglia in the brain. How can we understand whether or how microglia contribute to autism if we do not yet understand their normal biology?

Model lessons:

A flurry of studies in the healthy mouse brain have revealed novel and unexpected roles for microglia in brain development and the connectivity between neurons4. This new information may provide important insight into the mysterious link between microglia, the immune system and autism.

It was long thought that brain microglia differentiate from peripheral macrophages, immune cells that engulf invaders, that enter the brain after birth. This dogma was recently challenged when a landmark mouse study found that the majority of ‘resident’ microglial cells derive from myeloid-lineage precursorcells in the yolk sac and migrate into the brain very early in embryonic development5.

Microglia are therefore in the right place at the right time to influence a wide range of developmental processes that, if performed incorrectly, could contribute to autism. Indeed, studies published in the past few years implicate microglia in the generation of new neurons6, programmed cell death7, 8 and the development of neuronal junctions, orsynapses9.

In fact, microglia mediate synaptic pruning, a developmental process necessary for formation of precise synaptic circuits, in which inappropriate synaptic connections are eliminated9, 10. In several regions of the postnatal brain, microglia help sculpt developing synaptic circuits by engulfing, or phagocytosing, small bits of axons (the long bodies of neurons) and dendrites (their signal-receiving branches).

Mutations that disrupt microglial phagocytosis during development have a long-term impact on brain connectivity. This suggests that activated phagocytic microglia are necessary for proper synapse development.

Synaptic pruning is likely to be only the tip of the iceberg. Microglia also release an array of growth factors and neuromodulators that may influence brain development. Microglia dysfunction during brain development could, directly or indirectly, contribute to synaptic connectivity defects and the underlying biology of autism.

What is the basis of microglia dysfunction in autism? One possibility is that genetic mutations directly affect microglia development or function. Researchers have studied this in Rett syndrome, a disorder with many features of autism. Rett syndrome is caused by a mutation in MeCP2, and microglia lacking MeCP2 release abnormal levels of neurotransmitters and inhibit the development of neurons11.

MeCP2-deficient microglia also have impaired phagocytosis, which may prevent the clearing away of dying cells and debris in the Rett brain12. Strikingly, many of the classic symptoms of the disorder were arrested in a mouse model of Rett syndrome after a bone marrow transplant that allowed for the infiltration of healthy, normal microglia into the brain.

Genes to environment:

Other studies provide further compelling evidence that genetic disruptions in microglia can contribute to symptoms relevant to autism — at least in mice. For example, specific mutations in the HOXB8 gene in microglia results in severe obsessive-compulsive-like behaviors in mice13. And defects in the microglia-specific immune-related gene TREM2 cause social inhibition and dementia in Nasu-Hakola disease, a rare disease that leads to bone cysts14.

It is also possible that environmental factors alter microglia function and indirectly influence brain development and synaptic connectivity. Microglia are extremely responsive to inflammatory signals. Environmental conditions that lead to systemic or local inflammation, such as prenatal infection, could have major consequences for how microglia develop and function when the brain is wiring up.

Autism may result from the interaction between certain mutations, such as those in synaptic proteins, and environmental risk factors.

A 2011 study looking at gene expression in the postmortem brains of individuals with autism revealed two sets of co-expressed genes in autism: genes that influence neuronal signaling, and those that code for immune proteins and proteins that function in non-neuronal brain cells, such as microglia15. This suggests that genetic and environmental abnormalities converge in autism.

Consistent with this idea, epidemiological and animal studies suggest that autism is associated with immune system activation and dysfunction16, 17.

Recent advances in tools for imaging and manipulating microglia will be helpful for studying these mysterious immune cells in autism mouse models. Animal studies are likely to uncover candidate mechanisms and pathways, as well as biomarkers of microglial dysfunction that could then be tested in postmortem autism brains.

A better understanding of when and where microglia become dysfunctional in mouse models may provide insight into their function in circuits or brain regions that are relevant to autism, and may ultimately unveil new therapeutic targets.

Beth Stevens is assistant professor of neurology at Harvard Medical School.

References:

1: Perry V.H. et al. Nat. Rev. Neurol. 6, 193-201 (2010) PubMed

2: Ransohoff R.M. and V.H. Perry Annu. Rev. Immunol. 27, 119-145 (2009) PubMed

3: Suzuki K. et al. JAMA Psychiatry 70, 49-58 (2013) PubMed

4: Kettenmann H. et al. Neuron 77, 10-18 (2013) PubMed

5: Ginhoux F. et al. Science 330, 841-845 (2010) PubMed

6: Sierra A. et al. Cell Stem Cell 7, 483-495 (2010) PubMed

7: Marín-Teva J.L. et al. Neuron 41, 535-547 (2004) PubMed

8: Cunningham C.L. et al. J. Neurosci. 33, 4216-4233 (2013) PubMed

9: Schafer D.P. et al. Neuron 74, 691-705 (2012) PubMed

10: Paolicelli R.C. et al. Science 333, 1456-1458 (2011) PubMed

11: Maezawa I. and L.W. Jin J. Neurosci. 30, 5346-5356 (2010) PubMed

12: Derecki N.C. et al. Nature 484, 105-109 (2012) PubMed

13: Chen S.K. et al. Cell 141, 775-785 (2010) PubMed

14: Thrash J.C. et al. Neurochem. Res. 34, 38-45 (2009) PubMed

15: Voineagu I. et al. Nature 474, 380-384 (2011) PubMed

16: Saxena V. et al. PLoS One 7, e48835 (2012) Pubmed

17: Goines P. and J. Van de Water Curr. Opin. Neurol. 23, 111-117 (2010) PubMed


  • passionlessDrone

    Hi Beth Stevens –

    Nice article!

    The paradoxical nature of an ‘activated’ state of microglia and a lack of neurodegenerative features in autism has interested me for a while.

    A few things have occurred to me, perhaps the state of activation in autism is qualitatively different than what we see in degenerative disorders, but our filters are not (yet) adequately powered to make the distinction across the gradient of microglial activation. I’ve also wondered if a state of early life glial activation leads to a loss of opportunity effect at synapse pruning time; in other words, it isn’t the factors being released by the pheynotypically altered microglia that is the ‘problem’, but rather, that they *aren’t* doing the job of optimizing the neural network that you only get gestionally and during infancy.

    Do you have any thoughts regarding an improved ability to discern activation phenotype may allow us to gain more insight into this? The in-vivo study was nice, but still a pretty blunt tool.

    *Environmental conditions that lead to systemic or local inflammation, such as prenatal infection, could have major consequences for how microglia develop and function when the brain is wiring up.*

    Perhaps the findings of increased maternal CRP during gestation and consequent autism risk are interacting with microglial proiliferation and programming through the same pathways? This would also seem to be in line with findings on maternal obesity and/or metabolic syndrome as risk factors. Of course, if true, this would have some rather profound implications for the incidence question. . .

    Anyway, enough rambling. Thanks for the write up!

    – pD

  • David day

    Finally someone doing right research… Autism = Inflammation period…how

    1. Mother low vitamin D
    2. Child born with immune deficiency (low vitamin D, virus/lyme/h. pylori/yeast/babesia etc).

    please speed up the solution! Give a break to Autism Parents.. Including me…

  • David Day

    One more important thing to add

    Allergy! Alergy! – IgE/IgG/food intolerance… all points to immune system.

    Reduce inflammtion eventually recovering autism kids…

    • SAM

      When I read comments by parents: I see a lot of similarity bewteen what they experience with their child: Immune system , Allergies, IEG, Igg count high and food pickiness.

      I know of this non verbal autism boy, who varies in terms of behavior constantly. Very smart kid on Ipad, but to many people he sounds very dumb. I know for a fact after so many close interaction, there is another biological process here in play regression and upgression (LOL new word). But when the regression period occurs, this boy searches for medication as if he feels the process is coming. It is heartbreaking since we cant help him.
      During regression, he pees in his pants, stims, lethargic and so many weird thing he does.

      But when he is in upgression, he is a very normal kid. As if the connection within brain are just there…but something is at a miss.

      Please hepl these kids my dear scientific people

  • Katie Wright

    This makes perfect sense
    Great post
    This perfectly describes my son’s autism trajectory except the acute inflammatory was POSTnatal.
    Fine, healthy, talkative toddler than series of infections, adverse vaccine reactions leading to febrile seizure, loss
    of language and all skills.

    • SAM

      You know the worse thing is that, these sick kids like the boy I described above, since his diagnosis….he has been evaluated, researched 2 times for autism< one the autism evaluation documents and the second a blood sample for genetic research led by ERIC FOMBONNE. I mean no wonder there are hardly anywhere with autism. Its like they are doing their reseatrch on petri dishes in their labs and not looking at the patients themselves, regrouping them accoriding to their subtypes(Aspergers, classic etc). It is very frustrating. Autism + So many associated medical conditions for 10 years and they want to find the answer with one blood test-genetic field. I dont psychology, but I know in this way they are on the wrong tracks...Maybe get rid of Eric Fombonne and Al and start new with fresh pair of eyes.

  • ASD

    It’s also interesting that C-reactive protein levels in ASD children and children with allergic manifestations are significantly raised indicating also a chronic inflammatory process in those cohorts.

    So much information to untangle but the immune system and how it functions or dysfunctions seems to be of paramount importance.

  • Sarah

    Wonderful article! As a parent, I am thrilled that scientists are honing on microglia links to autism. I believe microglia activity in the brain is key to unlocking autism and other neurodegenerative disorders such as schizophrenia. Research on microglia links to neuropsychiatric disorders will also open up a window to treatments. Please watch this fascianting interview with Dr. Mario Capecchi, a Nobel prize winning geneticist who has done research on OCD behavior in mice and mental illness specifically focusing on the microglia. Capecchi says: “defective microglia, output defective behavior”

    “Utah scientist makes breakthrough in mental illness research” (click on FULL interview):

    http://www.ksl.com/?nid=148&sid=10947928

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