Inflaming inflammation and autism: linking microglial activation and neuronal activity

It has been quite a few weeks since the publication of the paper by Simone Gupta and colleagues [1] (open-access) talking about "observations [that] provide pathways and candidate genes that highlight the interplay between innate immunity and neuronal activity in the aetiology of autism."

I'm a wrecker. I wreck things, professionally. I mean.

At the time of publication in early December (2014), there was quite a bit of media interest in the findings as per reports such as this one and this one. The watch-words were 'inflammation', 'brain' and 'immune response' as per the discovery that microglia - the constant gardeners - might play quite an important role in the process of inflammation or at least "implicating dysregulated microglial responses in concert with altered neuronal activity-dependent genes in autism brains."

The Gupta paper is open-access so no need for the long explanation from me. Still a few points are worth mentioning bearing in mind my novice status in this area:

• The name of the game was transcriptomics, yet another -omic to add to your growing -omic dictionary, this time looking at "the complete set of RNA transcripts that are produced by the genome, under specific circumstances or in a specific cell."
• Said method was applied to RNA sequencing in "autism brains" or at least specific parts of the brain donated by families of 32 deceased people with autism and 40 asymptomatic controls. If you are really interested, cortical samples were analysed looking at some regions already discussed in the autism research literature (see here). I apologise for the cold, scientific discussions by the way given first and foremost those brain samples were very precious offerings.
• Differences in genetic expression were found between the groups which were further examined via gene ontology (GO!) and something called "weighted gene correlation network analysis" which as the name suggests looks at correlating genes which are co-expressed "to identify discrete gene modules based on co-expression between genes." One of the best hits the authors got was in relation to "enrichment for M2-microglial cell states... and the GO term ‘Type I Interferon pathway’". The type I Interferon pathway includes the name 'interferon' which implicates immune function (see here).
• Ergo, "evidence for type I interferon and M2-activation state abnormalities in autism that may lead to a variety of pathologic and phenotypic consequences." The authors speculate that "M2-activation state microglia genes" are potentially 'driven' by the interferon response which brings us back to those headlines about brain inflammation being 'common' in autism. The idea that neuronal activity-dependent genes might also be 'affected' by this state unites immune function and brain development with at least the cohort of cases of autism in mind. 
• I might also add that whilst interest focused on the microglia - interferon connection, the GO category enrichment data also picked up a few other potentially interesting connections including "defense response to virus" and "response to virus". Indeed, the authors summarised by suggesting: "These data provide support for a mechanistic connection for viral-infection hypotheses... for autism with neural over-growth hypotheses... through the novel identification of exaggerated M2 activation states in autism brain tissue." Parts of Johns Hopkins, where quite a few of the authors are based, have some speciality in this area as per other research teams (see here) so are perhaps ideally placed to follow this work up as and when required.

Accepting that studying brains from the deceased is still an area fraught with some methodological issues not least because the diagnosis of autism very rarely exists in clinical isolation some comorbidity of which can impact on the reasons for early mortality, inflammation and autism already has quite a bit of research history when it comes to the peer-reviewed arena. The genetics of the immune system being implicated in autism is also not new news as per other entries on this blog (see here) and my already linking to some discussions about the Nardone paper [2] last year (2014) also implicating epigenetic processes too. Microglia and autism? Well again, been there and seen that similarly applies (see here).

Interestingly, in some of the accompanying press attached to the Gupta study is the suggestion that future work might look to "find out whether treating the inflammation could ameliorate symptoms of autism." Approaching such a sentiment with some degree of caution, I'd be minded to suggest that such ideas seem to follow a pattern in psychiatry these days (see here) further to the idea that the chemistry of inflammation seems to be connected to at least some autism [3] (see here and see here too). Peter over at the Epiphany blog has, as well as covering the Gupta study, talked about quite a few ways and means that one might go about 'treating' such inflammation. What I would perhaps add - alongside my caveat about this blog not giving medical or clinical advice - is that rather than just focusing on the agents potentially 'causing' inflammation, one might also look at the counter-balance systems also present, as per my discussions on some fairly recent work from Harumi Jyonouchi and colleagues [4] and the so-called anti-inflammatory cytokines such as IL-10 (see here). Just a thought...

The Blue Danube to close... (music starts at 1min 40secs)

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[1] Gupta S. et al. Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nat Commun. 2014 Dec 10;5:5748.

[2] Nardone S. et al. DNA methylation analysis of the autistic brain reveals multiple dysregulated biological pathways. Transl Psychiatry. 2014; 4: e433

[3] Mead J. & Ashwood P. Evidence supporting an altered immune response in ASD. Immunol Lett. 2015 Jan;163(1):49-55.

[4] Jyonouchi H. et al. Cytokine profiles byperipheral blood monocytes are associated with changes in behavioral symptoms following immune insults in a subset of ASD subjects: an
inflammatory subtype? Journal of Neuroinflammation. 2014, 11:187

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Gupta S, Ellis SE, Ashar FN, Moes A, Bader JS, Zhan J, West AB, & Arking DE (2014). Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nature communications, 5 PMID: 25494366