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What does the brain's immunity have to do with autism?

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Greg Boustead
4 March 2013

A growing body of evidence suggests that microglia — cells traditionally thought of as the brain’s support system — may play a critical role in autism and related disorders. In December, the Simons Foundation Autism Research Initiative brought together a group of scientists studying this connection using a variety of approaches. 

Read our report on the workshop here »              

After reviewing the latest data and hypotheses explaining the connection, the attendees attempted to define the next steps for exploring how the brain’s immunity might be involved with autism.

Jonathan Kipnis discussed his groundbreaking study showing that transplanting healthy bone marrow into mice that model Rett syndrome  rescues some of the symptoms of the disorder. Yet, many questions remain about whether and what roles microglia play in autism.

What do you think?                                                             

  • Are the elevated levels of microglia observed in autism brains causing symptoms of the disorder, or are they the reaction to an unhealthy environment? Clinically speaking, should we ultimately be looking to knock microglia down, or are they a compensatory response that we should enhance?

  • Anecdotal evidence suggests that autism symptoms become less severe during periods of fever. Could microglia play a role in this phenomenon? If so, how?

  • What markers exist for measuring or estimating levels of microglia in people with autism or other disorders?


Share your thoughts in the comments section below.

Or dig deeper and visit the section dedicated to this workshop discussion in the moderated SFARI Forum, where you can respond to existing threads and pose your own questions to the researchers who presented at the workshop.

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News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.

Comments

Name: passionlessDrone
6 March 2013 - 7:30PM

Hi Greg Boustead -

Those are some heavy questions!

"Are the elevated levels of microglia observed in autism brains causing symptoms of the disorder, or are they the reaction to an unhealthy environment?"

My thoughts are that they are likely participating in autism pathogenesis. As you mention, an altered microglia population appears to be present in several other neurological disorders. If we want to explore a non pathogenic role for the immunological associations found in autism, we also need to provide a context on why these other detrimental conditions also show signs of immune activation. Of course, we cannot discount the possibility that altered microglia function could be responsible for some of the other things we see in some particular cases of autism that are 'good', like improved spatial capacities or memory.

The animal models, imprecise as they are, tell us again and again that a state of persistently altered microglia can be achieved through disturbances (i.e., early life immune challenge) known to be associated with autism. In these instances, there isn't anything consistent with the 'traditional' models of activation of microglia such as injury or CNS infection. If I understand correctly, there is actually relatively little evidence of brain 'damage' per se in the autism population, and excepting one quircky Persico study, no evidence of an ongoing infection. Did the researchers at the meeting discuss any potential markers of an unhealthy environment that could be triggering the microglia changes observed in autism?

Did any of the panelists discuss mechanisms by which different microglial colonization and organization of the brain may be achieved in autism?

"Clinically speaking, should we ultimately be looking to knock microglia down, or are they a compensatory response that we should enhance?"

I've yet to see any research on trying to increase the microglial response, in any type of model, do you know of any examples?

It may be that trying to tamper down microglial activation by the time we know it is a problem is akin to shutting the barn door after the horse has gotten out. If microglial activation is present in utero and during infancy, and if that altered phenotype hinders the process of synaptic optimization during that timeframe, putting a halt to microglial activation after those once in a lifetime events have occurred isn't going to allow the brain to go back in time. A persistent lost opportunity. This time sensitivity, may be, why the Kipnis study observed a time dependent effect of microglia replacement rescue; animals getting irradiated at day 45 didn't have the same neurochemical cocktail in place to facilitate appropriate synaptic pruning, but animals getting radiated at day 15 got their chance. This is, of course, wildly speculative.

I'd note that we have (at least) one 'gold standard' study involving reducing the peripheral immune response that found improved behaviors; i.e.,

Celecoxib as adjunctive treatment to risperidone in children with autistic disorder: a randomized, double-blind, placebo-controlled trial [Psychopharmacology (Berl). 2013 Jan;225(1):51-9. doi: 10.1007/s00213-012-2796-8. Epub 2012 Jul 11.]

The direct data implicating cox2 inhibitors affecting microglial activation is sparse, but the general pattern of changing inflammation outside the CNS and seeing corresponding changes of microglia activation inside the CNS is much stronger. Other studies indicate that N-actylcysteine participates in dampened microglial activation after injury, and a double blind, placebo control study of that supplement in autism also showed beneficial effects.

Unfortunately, at this time, we don't have any way of knowing if these treatments observed benefit due to altered microglia function, but the underlying mechanisms are available. I do think you could probably design an animal experiment for that, however. . . . .

"Anecdotal evidence suggests that autism symptoms become less severe during periods of fever. Could microglia play a role in this phenomenon? If so, how?"

Well, if this phenomena is real, and if microglia are participants, perhaps the induction of a fever involves a different activation profile of the microglia? I wonder,did any of the panelists speak towards illuminating the 'activation profile' of the microglia in autism; my reading tends to tell me that there is a continuum of microglia morphology as opposed to an off/on switch. Was there a discussion of experiments designed to more accurately profile the microglia?

Those are some of my thoughts anyways.

Note: tried to post some questions to the other page, but got the dreaded ascii error

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