Monday, 20 August 2012

Autism and microglia

An interesting paper has appeared by Beumer and colleagues* with the grandiose title: The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes. It's an intriguing paper linking specific actions of the immune system on brain areas in connection to various conditions including depression and schizophrenia via a biological entity that seems to be gaining some research interest: microglia.

On the basis of this publication I therefore resisted no longer and decided to set off on the voyage of discovery that is a possible role for microglia in cases of autism. Please understand that I undertake this post with some trepidation as my skill set does not readily encompass the hows and whys of microglia, so be at the ready with that rather large pinch of salt.

Quite a good overview of microglia is here by Kettenmann and colleagues** (full-text) alongside some discussion on their 'constant gardening' effect in this piece by Virginia Hughes*** (full-text). Apparently constituting as much as 10% of the cells of the central nervous system, microglia derive from cells of the immune system and activate in response to injury or inflammation. More than that however, there is some emerging evidence that microglia might also play a role in the pruning process which the developing brain undertakes during the early years and perhaps beyond.

With autism specifically in mind, I've already linked in previous posts to an interesting blog piece from Paul Patterson on microglia potentially eating synapses in autism as a consequence of some interesting research suggesting increased microglial activation in some cases of autism****. I draw your attention also to another interesting blog post on the SFARI website which strengthens a possible connection between microglia and a mouse model of Rett syndrome, noting also the controversial issue of bone marrow transplant as a potential route to "generating healthy microglia". I might add that I am not getting too obsessed with stem cells and the such like, but in light of Prof. Patterson's recent paper, one has to keep an open mind.

Other research on microglia and autism:

  • Starting from the early days of the PubMed catalogue on this topic a few familiar names crop up with microglia in mind. Andrew Zimmerman and colleagues***** (he of the 'can you grow out of autism' research) talked about neuroglial activation and neuroinflammation quite a few years ago. They reported "marked activation of microglia" alongside several other inflammatory related findings in the brains of people with autism. Similar follow-up studies from this research group also talked about paradoxical lower levels of quinolinic acid in cerebrospinal fluid which  brings us back to everyone's favourite aromatic amino acid, tryptophan. I'll leave that for now.
  • Propionic acid (PPA), the topic of quite a recent blog post, also gets a look-in with microglia in mind as per the paper by Derek MacFabe and colleagues******. They report that during their 'inject PPA into rodent brain' experiments, increases in activated microglia was one of the effects contributing to the neuroinflammatory process described. Whilst I would love to be able to say this might tie into the short chain fatty acid findings also talked about with PPA and autism in mind (here), it is probably not unexpected that PPA administration so directly and at such quantities would provoke a reaction from microglia given their activation at the first sight of any foreign invaders.
  • Other research speculates on the role of microglia and autism (here, here and here), in some cases speculating on the potential environmental factors which may exacerbate microglial priming. I was also drawn to this paper by Schwarz & Bilbo******* who discuss how gender differences in the colonisation and function of glia may offer some interesting explanations for the gender differences seen in conditions like autism, acknowledging that glia includes more than just microglia.

There is still some way to go with regards to the microglia-autism story but so far the research base could be described as very interesting. Inflammation, as I have said before, seems to be playing many hands in at least some cases of autism. Whilst the chicken-and-egg debate about immune function and autism continues, there is little doubt that for some, immune involvement - whether mediated/described by microglia activation, circulating cytokines or other markers of inflammation and immune over- or -under activation, seems to be a facet of symptom presentation. The puzzle is still far from complete however.

Finally, there is the question about what can be done about over or chronic activation of microglia. Reiterating my caveat about not giving medical advice or anything approximating such advice and aside from the bone marrow transplant data already touched upon, I was interested to read the various literature on the effect of administration of the tetracycline antibiotic, minocycline on microglial activation as per studies likes this one and this one (both full-text). Accepting that certain antibiotics might be a bit of a double-edged sword for some cases of autism (see this post) as well as such compounds having other, more recognised antimicrobial action - potentially important in some cases of autism - it does make me wonder whether targeting such interventions at activated microglia at a critical time might be a research area worth investing in.

To finish, I'm in the mood for some Ska. So without further ado, the Specials and Too Much Too Young.

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* Beumer W. et al. The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes. Journal of Leukocyte Biology. August 2012.

** Kettenmann H. et al. Physiology of microglia. Physiological Reviews. 2011; 91: 461-553.

*** Hughes V. Microglia: the constant gardeners. Nature. 2012; 485: 570-572.

**** Morgan JT. et al. Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism. Biological Psychiatry. 2010; 68: 368-376.

***** Vargas DL. et al. Neuroglial activation and neuroinflammation in the brain of patients with autism. Annals of Neurology. 2005; 57: 67-81.

****** MacFabe DF. et al. Neurobiological effects of intraventricular propionic acid in rats: possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders. Behavioral Brain Research. 2007; 176: 149-169.

******* Schwarz JM. & Bilbo SD. Sex, glia, and development: Interactions in health and disease. Hormones & Behavior. February 2012.

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ResearchBlogging.org Beumer W, Gibney SM, & Drexhage RC (2012). The immune theory of psychiatric diseases: a key role for activated microglia and circulating monocytes J Leukoc Biol. DOI: 10.1189/jlb.0212100

4 comments:

  1. Oh snap! Oh snap!

    Regarding gardening and pruning and whatnot, I think one important thing to remember is that these actions occur when the microglia are in a so called resting state; i.e., when they are morphologically different than when they are 'activated' (either chronically activated or not). [Of course, the 'activated' or 'resting' terminology are really just crutches based on our rather impaired ability to detect what they little buggers are doing in there in vivo until very recently].

    That being said, if chronic microglial activation occurs in a subset of people with autism and said chronic activation begin early in life, it could impact synaptic pruning as a kind of bystander effect; instead of pruning like a good old microglia, the microglia are too busy freaking out. I think we should be less worried about the microglia eating synapses, and more worried about them not eating synapses during fetal and early postnatal life.

    For a really neat paper on the developmental impacts of microglia participation, you might try out:

    Microglia in the developing brain: a potential target with lifetime effects

    Among other nuggets, there is evidence that microglia are extremely long lived and have very low turn over rates over the lifespan. Not only that, there is also evidence that there are periods wherein they can 'learn' (or be programmed) into a specific function. Their effects in this regard also appear to have large postnatal influences.

    This is one potential reason they seem to be candidates for time dependent developmental impacts; you get them once, early in life, at a time when once in a lifetime processes are being performed. If their trajectory is perturbed, they can stay perturbed.

    Regarding the Bilbo / Schwartz paper, nice catch! There are also some papers regarding the population density of microglia in the autism realm (i.e., Microglial activation and increased microglial density observed in the dorsolateral prefrontal cortex in autism and Microglia in the Cerebral Cortex in Autism. Considered within a context of a sex and time dependent of a once in a lifetime migration of microglia into the CNS, these are some pretty neat findings.

    Great post!

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  2. Thanks pD.

    Just reading around the whole microglia story with autism (and lots of other things in mind) it seems as though this is quite an interesting area for further study. That and other glial cells like astrocytes (a separate post on its own).

    Interesting thoughts about the pruning effects of microglia. Takes me back to some interesting research on S100B and autism also: http://www.jneuroinflammation.com/content/pdf/1742-2094-9-54.pdf




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  3. Very over my head, but very interesting! I thought of Martha Herberts book The Autism Revolution. She talks a lot about diets in the book. She doesn't recommend specific diets, it more to tell how diet/nutrition affects the brain, especially glial cells, which might explain why parents see the improvements in their kids with diet change.
    And the Ska... I might have to dust off my Mighty Mighty Bosstones.

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  4. Thanks Mrs. Ed.

    Martha Herbert is really making some waves with the new book and certainly as a pediatric neurologist, knows what she is talking about when it comes to all things glial. I on the other hand, am still on a learning curve when it comes to brains and stuff but found the microglia-immune link to be very, very interesting.

    As for the Bosstones - I'd forgotten about them... someday, I suppose (remembering Clueless the movie also).

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