Immune endophenotypes in paediatric autism

Today I'm serving up the paper by Milo Careaga and colleagues [1] for your blogging delight, who concluded that: "Children with ASD [autism spectrum disorder] may be phenotypically characterized based upon their immune profile." Further that there may be: "several possible immune subphenotypes within the ASD population that correlate with more severe behavioral impairments."

With many thanks to Natasa for the paper, participants - 50 boys with a median age of 3.2 years diagnosed with an ASD and enrolled "through the Autism Phenome Project (APP) study" and who were free of any "major immune modifying medications" - provided a blood sample. A similar process was employed for a smaller group of typically developing (asymptomatic) control group (n=16). Said blood sample went through various processes to harvest peripheral blood mononuclear cells (PBMC) which were then 'stimulated' to provoke an immune reaction via "either lipopolysaccharide (LPS) or phytohaemagglutinin (PHA)." Various cytokines were then assayed for in the stimulated PBMC and results analysed according to immune responses and behavioural outcomes.

Results: as per the opening paragraph, there was potentially something to see in the findings added to a more general role for cytokines in relation to autism [2]. Those children with ASD who presented with a more 'pro-inflammatory' cytokine profile in their stimulated blood results "showed more impaired developmental and behavioral scores, as well as increased problems with sleep and aggression." That pro-inflammatory cluster by the way (n=22) tended to show significantly increased production of cytokines such as IL-6 for example, than those children with autism (n=28) "who displayed a less robust response to LPS." Ergo, perhaps more to see and certainly more investigations required in these days of plural autisms.

I was taken by one particular sentence included in the conclusion of the Careaga paper: "Although immune abnormalities were first described in ASD over forty years ago, no consensus has been reached as to what constitutes clinically significant immune dysfunction in ASD." As per quite a bit of autism research, sweeping generalisations about this, that or t'other 'causing' autism or being part and parcel of autism have been a big contributor to the noticeable lack of progress on knowledge about autism and where required and wanted, what can be done to ameliorate the more disabling aspects including that related to comorbidity (see here). Realisation that 'autism' is probably better described as providing an umbrella term for various different conditions on a genetic and molecular level is making some headway these days (see here) including that linked to immune function (see here for example). This might have important implications for intervention (see here) as per other recent results that I'll be musing over soon.

As part of a broader realisation that immune function and psychiatry probably show a lot more connections than many people first realised (see here), I think we are seeing a shift in knowledge here. As per the Careaga results, the idea that there may be distinct clusters within the presentation of autism linked to immune function, opens up a whole new world of more 'targeted' inspection and intervention which, added to other similar phenotype work (see here), is probably an important direction for autism research...

Music: Duran Duran - Pressure Off feat. Janelle Monáe and Nile Rodgers.

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[1] Careaga M. et al. Immune endophenotypes in children with autism spectrum disorder. Biological Psychiatry. 2015. 10 Sept.

[2] Krakowiak P. et al. Neonatal Cytokine Profiles Associated with Autism Spectrum Disorder. Biol Psychiatry. 2015 Aug 14. pii: S0006-3223(15)00655-1.

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Milo Careaga, Sally Rogers, Robin L. Hansen, David G. Amaral, Judy Van de Water, & Paul Ashwood (2015). Immune endophenotypes in children with autism spectrum disorder Biological Psychiatry : 10.1016/j.biopsych.2015.08.036

Inflammation impairs social cognitive processing

A quote to begin: "acute inflammation can lead to decreases in the ability to accurately and reliably comprehend emotional information from others."

It comes from the article published by Mona Moieni and colleagues [1] who examined a concept familiar to many people with a connection to autism either personally or professionally: Theory of Mind (ToM). Rather interestingly, Moieni et al "examined whether exposure to an experimental inflammatory challenge led to changes in ToM." Inflammatory challenge refers to the artificial induction of a state of inflammation via the use of something called endotoxin, something I've covered under another name previously on this blog (see here).

As part of a larger research project on inflammation-induced depressed mood (see here) researchers set about looking at social cognition under inflammatory-inducing and placebo conditions specifically based on the "Reading the Mind in the Eyes (RME) test". The RME test has quite a firm foundation in autism research [2]. Their results indicated that using the RME test as a sort of measure of ToM "endotoxin (vs. placebo) led to decreases in performance on the RME test from baseline to the peak of inflammatory response, indicating that acute inflammation can lead to decreases in the ability to accurately and reliably comprehend emotional information from others."

With the caveats that (a) this wasn't a study of people with autism (or at least not those diagnosed with autism) and (b) acute inflammation may not be the same as chronic inflammation, these are intriguing results potentially overlaying onto several other research areas. Autism and inflammation is something that I'm quite interested in on this blog as per the idea that physiology and psychology might not be some far apart in certain cases/types of autism (see here). That other somatic manifestations might also be linked to inflammatory processes with autism in mind (see here) is something else to mention.

I hold back from saying that all those with autism who 'fail' ToM tasks are somehow in a state of inflammation given that this is a complicated area (see here). As per my previous ramblings, I'm also not necessarily the greatest fan of the sweeping generalisations made about ToM when it comes to autism (see here). Particularly when one looks at the way that ToM is examined in relation to autism [3] and how ToM issues cross quite a few different labels [4] some of which might overlap with autism (see here).

Still, if there is the remotest possibility that the physiological state of acute inflammation might correlate with issues with mentalising or completing mentalising tasks, I'd be minded to suggest that future work on ToM might be minded to take this into account. Likewise, in all those studies looking at inflammatory processes linked to something like autism, measuring ToM before and after could represent an interesting parameter when looking at potential interventions...

Some music then... The Wedding Present and My Favourite Dress.

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[1] Moieni M. et al. Inflammation impairs social cognitive processing: A randomized controlled trial of endotoxin. Brain, Behavior, and Immunity. 2015. May 10.

[2] Baron-Cohen S. et al. The "Reading the Mind in the Eyes" Test revised version: a study with normal adults, and adults with Asperger syndrome or high-functioning autism. J Child Psychol Psychiatry. 2001 Feb;42(2):241-51.

[3] Iao LS. & Leekam SR. Nonspecificity and theory of mind: new evidence from a nonverbal false-sign task and children with autism spectrum disorders. J Exp Child Psychol. 2014 Jun;122:1-20.

[4] Chung YS. et al. A meta-analysis of mentalizing impairments in adults with schizophrenia and autism spectrum disorder. Schizophr Bull. 2014 May;40(3):602-16.

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Moieni M, Irwin MR, Jevtic I, Breen EC, & Eisenberger NI (2015). Inflammation impairs social cognitive processing: a randomized controlled trial of endotoxin. Brain, behavior, and immunity PMID: 25770082

A rat model of early immune stimulation

It took me a few a reads of the paper by Anna Kubesova and colleagues [1] (open-access) to understand just how potentially important their findings might be to various conditions including schizophrenia and autism.

Reporting results of a study where "early immune stimulation induced by postnatal systemic administration of LPS [lipopolysaccharide]" was performed in rats, researchers examined various potential effects on "the levels of monoamines (dopamine, serotonin) and their metabolites, and the levels of the main excitatory and inhibitory neurotransmitters glutamate and γ-aminobutyric acid (GABA) in the brain" and "activation of the kynurenine pathway of tryptophan metabolism." Brain morphology, and in particular, hippocampal volume was also the topic of some investigation.

Before coming to the results, a few additional points are worthwhile mentioning. Rats were the participants of choice in this study. I say again, rats were the participants of choice. The use of the word 'postnatal' to denote how LPS - one of the artificial immune activation weapons of choice - was administered after birth was also of initial interest to me, given that prenatal immune activation (that is immune stimulation administered to pregnant mother mice/rats/monkeys and then analysis of the effects on offspring after birth conducted) has been where the majority of the research has been done in this area (see here). The authors do comment on this however: "The early postnatal period in rats corresponds approximately with the third trimester of human brain development" although the difference between injecting LPS into offspring rats vs. pregnant rats is still present. LPS was also administered via intraperitoneal injection, that is the into the peritoneum, the tissue that lines the abdominal wall.

OK, so what did they find? Well, quite a bit, for example:

• Analysis of neurotransmitters and metabolites in brain and plasma of LPS treated and control rats were carried out by "liquid chromatography combined with electrospray ionization tandem mass spectrometry (UHPLC–ESI-MS/MS)" based on methods reported in a previous study [2]. Curiously however, authors chose to present a HPLC trace (Figure 1) showing the separation of the analytes over and above the more superior mass spec results. I would have preferred to have seen those any day.
• The authors reported: "significantly increased levels of DOPAC [3,4-dihydroxyphenylacetic acid], HVA [homovanilic acid] and 5-HIAA [5-hydroxyindolacetic acid] and decreased levels of 5-HT [serotonin] and 3-MT [3-methoxytyramine] in each measured brain area in LPS treated animals compared with the control group."
• Further: "There were significantly increased levels of GLU [glutamate] in each measured brain area, decreased levels of GABA in the hippocampus and a decreasing trend of GABA in the prefrontal cortex in LPS treated animals compared with the control group."
• And also: "We detected significantly increased levels of TRP [tryptophan], KYN [kynurenine], 3-OH-KYN [3-hydroxykynurenine] and QUIN [quinolinic acid] in each measured brain area and plasma in LPS treated animals compared with the control group."
• Differences in brain morphology are also reported as per the finding: "early postnatal LPS administration led to a volume reduction of the hippocampus."

And with all that, again bearing in mind that this was a study of rats, the authors conclude that: "Our results suggest a pathogenetic link between early immune stimulation and neuropsychiatric disorders such and schizophrenia, mood disorders, anxiety disorders, autism, Parkinson’s disease and Alzheimer’s disease."

These are interesting results that require both replication and follow-up. Of all the findings presented as potentially being connected to early immune stimulation, I was particularly interested in those related to kynurenine and some previous work talking about a kynurenic acid hypothesis of schizophrenia (see here). Kubesova and colleagues do talk about their results not necessarily fitting in with the idea that elevated kynurenic acid (KYNA) might be linked to at least some cases of schizophrenia [3] as per the fact that they: "did not find any change of KYNA levels in the brain or plasma compared to the controls." Activation of this pathway and a link with those dastardly pro-inflammatory cytokines (see here) (which were surprisingly not measured in the current study) might however offer some important clues on how immune activation links into some of the metabolites of little 'ole tryptophan and where future work might go from there.

The findings of elevated levels of tryptophan in both plasma and brain of LPS treated animals and reduced levels of tyrosine hydroxylase positive cells in certain parts of the brain was also something which got me thinking. Tyrosine hydroxylase as one of the triad of aromatic amino acid hydroxylases (metabolising tryptophan, tyrosine and phenylalanine) is a valued user of something called tetrahydrobiopterin (BH4), a substrate which has been mentioned a few times on the blog with autism (see here), schizophrenia (see here) and more classically, phenylketonuria (PKU) (see here) in mind. Aside from the potential effect of immune activation on levels of tyrosine hydroxylase bearing in mind how this family of enzymes might not necessarily be too exclusive in what they metabolise [4], I'm wondering whether BH4 might be something else to look at in future work given it's already known-about link to immune activation [5] alongside say, levels of tryptophan hydroxylase too? Indeed, the fact also that higher levels of tryptophan were noted in LPS treated animals but lower levels of 5-HT (serotonin) in "each measured brain area" could be construed as offering further support for closer inspection of tryptophan enzyme chemistry in this immune related model.

I know animal studies such as this one have to be cautiously interpreted in terms of how well they extend to complex labels such as autism or schizophrenia, with their very wide degree of heterogeneity and important mix of comorbidities. This still doesn't stop me however from being really quite interested in where the Kubesova findings might eventually lead us. I might also link you to the paper from Luan and colleagues [6] and another area crying out for further study with maternal immune activation in mind...

Music: Nick Cave & The Bad Seeds with Red Right Hand.

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[1] Kubesolva A. et al. Biochemical, Histopathological and Morphological Profiling of a Rat Model of Early Immune Stimulation: Relation to Psychopathology. PLoS ONE. 2015; 10(1): e0115439.

[2] Najmanová V. et al. LC-ESI-MS-MS Method for Monitoring Dopamine, Serotonin and Their Metabolites in Brain Tissue. Chromatographia. 2011; 73: 143-149.

[3] Erhardt S. et al. The kynurenic acid hypothesis of schizophrenia. Physiol Behav. 2007 Sep 10;92(1-2):203-9.

[4] Roberts KM. & Fitzpatrick PF. Mechanisms of Tryptophan and Tyrosine Hydroxylase. IUBMB Life. 2013.; 65: 350–357.

[5] Neurauter G. et al. Chronic immune stimulation correlates with reduced phenylalanine turnover. Curr Drug Metab. 2008 Sep;9(7):622-7.

[6] Luan R. et al. Maternal Lipopolysaccharide Exposure Promotes Immunological Functional Changes in Adult Offspring CD4+ T Cells. Am J Reprod Immunol. 2015 Jan 30.

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Kubesova A, Tejkalova H, Syslova K, Kacer P, Vondrousova J, Tyls F, Fujakova M, Palenicek T, & Horacek J (2015). Biochemical, Histopathological and Morphological Profiling of a Rat Model of Early Immune Stimulation: Relation to Psychopathology. PloS one, 10 (1) PMID: 25602957

Bacterial infections and behaviour

I'm more than a little interested in bacteria on this blog. Indeed, quite a lot of chatter here has been dedicated to the various bacteria residing in our deepest, darkest recesses specifically with conditions like autism in mind. I'm also pretty interested in how other bacteria might also have the potential to do so much more than just affect a physical response. Take the issue of PANDAS (or PANS) as one example or even the notion of psychological development being linked to bacteria (in mice at least). Indeed, this piece in the New Scientist was a particularly interesting read for me (although I prefer the term psychobacteriomics...).

Garden of Earthly Delights @ Wikipedia 

Today's post deals with a triad of papers which are united in their suggestion that infection caused by bacteria may indeed have some important repercussions for conditions such as autism, schizophrenia and psychotic illness. So without further ado...

First we have the paper by Ousseny Zerbo and colleagues* who reported that although no overall "association between diagnoses of any maternal infection during pregnancy and ASD [autism spectrum disorder] was observed" in their cohort, women diagnosed with a bacterial infection during a hospital admission were "at increased risk of delivering a child with ASD". You can read more details about this study in the accompanying press release (see here) or media (see here). I should point out that this authorship group have some research form in the area of infection and autism as per my 'you give me fever' post.

Then we have the paper by Nielsen and colleagues** who, based on quite a large study group, reported that "individuals who have had a hospital contact with infection are more likely to develop schizophrenia". Further that: " Bacterial infection was the type of infection that was associated with the highest risk of schizophrenia (RR = 1.63; 95% CI: 1.47-1.82)".

Finally, the paper by Blomström and colleagues*** completes the triad and their suggestion of "a small but statistically significant association between hospital admissions for infections, in general, throughout childhood (0-13 years) and a later diagnosis of nonaffective psychosis" which "seemed to be driven by bacterial infection".

As you might already have noticed these are studies of association and correlation and so can't necessarily show causality (i.e. that bacterial infection caused autism or schizophrenia or psychotic illness). Indeed, given the complexity and heterogeneity present in these conditions, including quite a lot of chatter about spectrums, it would be foolhardy to pin it down to just one factor as being causative. I should also point out that the relative risk of bacterial infection being linked to autism, schizophrenia or psychosis were also quite low in these studies despite the connections being made.

That being said, the suggestion of a link between behaviour and a history of direct or indirect contact with bacterial pathogens is not something new. I've gone on (and on) about the concept of maternal immune activation and autism for example (see here and here) and the interesting data being generated in this area of investigation culminating with things like MAR autism and the recent leaky mice guts study. That alongside the fact that use of LPS (lipopolysaccharides) is a tool of choice when it comes to modelling bacterial infection on mouse models of autism or schizophrenia (see here). When it comes to specific agents harbouring bacteria, that's also been the topic of some discussion too (see here).

There is more to do in this area in terms of issues like tracking down exactly what types of bacteria might show more involvement in any relationship and the mechanism of effect (Inflammation? A link to those jumping genes?). Indeed, whether certain types of bacterial infection might be more commonly associated with parts of the autism or schizophrenia spectrums as per what we found on two occasions (here**** and here*****) when it came to the parent-reported frequency of impetigo in some cases on the autism spectrum. Just one example of where research might start looking.

Likewise, questions remain about the early treatment of bacterial infections and whether these might modify the risk of future development of the conditions being associated by these studies. Bear in mind however, that the use of antimicrobials (antibiotics) as the treatment of choice have also received some research attention both positive and not-so-positive (see here and here) when it comes to autism and schizophrenia.

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* Zerbo O. et al. Maternal Infection During Pregnancy and Autism Spectrum Disorders. J Autism Dev Disord. 2013 Dec 24.

** Nielsen PR. et al. Hospital Contacts With Infection and Risk of Schizophrenia: A Population-Based Cohort Study With Linkage of Danish National Registers. Schizophr Bull. 2013 Dec 30.

*** Blomström A. et al. Hospital Admission With Infection During Childhood and Risk for Psychotic Illness--A Population-based Cohort Study. Schizophr Bull. 2013 Dec 23.

**** Whiteley P. Developmental, behavioural and somatic factors in pervasive developmental disorders: preliminary analysis. Child Care Health Dev. 2004 Jan;30(1):5-11.

***** Whiteley P. et al. Trends in Developmental, Behavioral and Somatic Factors by Diagnostic Sub-group in Pervasive Developmental Disorders: A Follow-up Analysis. Autism Insights 2009:1 3-17

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Zerbo O, Qian Y, Yoshida C, Grether JK, Van de Water J, & Croen LA (2013). Maternal Infection During Pregnancy and Autism Spectrum Disorders. Journal of autism and developmental disorders PMID: 24366406

Autism, maternal immune activated mice and suramin

Avid followers of the autism research circuit must have noticed the increasing tide of studies looking at a possible role for maternal immune activation (MIA) in relation to risk of offspring autism spectrum disorder (ASD). It's a topic I've covered more than once on this blog; predominantly in relation to the work of people like Paul Patterson and his colleagues (see here), observations on things like C-reactive protein (see here) and the various ways to experimentally mimic such MIA in the mouse model of autism / schizophrenia / other for example (see here).

Squeakers @ Wikipedia  

So it is in this post that I'm serving a double helping of the MIA model of autism as per the publication of studies from Jared Schwartzer and colleagues from the MIND Institute* (open-access) and Robert Naviaux and colleagues** (open-access).

Both studies looked at the effects of artificial induction of MIA in the mouse model following poly I:C use as an immunostimulant. Thereafter the two studies went their separate ways as Schwartzer looked at the variable of mouse strain on the after-effects of MIA on offspring and Naviaux looked at the role of purinergic signaling.

I'll say right now that I am neither qualified nor experienced enough to go into these papers with any great detail. So I won't; instead a brief overview of each - bearing in mind their open-access status - and some interesting factoids which have already been mentioned in the autism research peer-reviewed domain which might tie into results.

The work of Schwartzer and colleagues basically "indicate[s] the need to consider how genetic predisposition may exacerbate or protect against the effects of environmental insults in the etiology of ASD". In other words, based on a mouse model looking at different strains of mouse, the specific genetic make-up of that mouse model might impact on offspring presentation after an artificial MIA event.

In their case they looked at the C57BL/6J and BTBR T+tf/J inbred mouse strains and concluded that the dangermouse that is the BTBR strain combined with the poly I:C stressor seemed to "be synergistic resulting in greater behavioral impairment than from either factor alone" when compared with the C57BL/6J mouse strain. Some interesting variables are noted including elevations in cytokines like IL-6 (see here) and IL-17 (see here) in the BTBR offspring mice compared to C57BL/6J mice alongside some sex specific behavioural differences. All in all, some very interesting observations; and on that sex-specific notion, not completely at odds with other work in this area (see here).

The work of Naviaux and colleagues - summarised quite well here - has definitely taken the interest of the media as per headlines such as 'New drug that may help reverse autism' or should that be 'Century old drug could beat autism'. I'm confused. The long-and-short of it is that based on the analysis of the MIA mouse model - C57BL/6J mice - there was a suggestion that "hyperpurinergia is a fundamental and treatable feature of the multisystem abnormalities in the poly(IC) mouse model of autism spectrum disorders". Treatable via "antipurinergic therapy (APT)" which in this study was via the drug suramin. The observant reader should immediately be comparing Schwartzer and Naviaux and the MIA mouse models chosen and results obtained.

Anyhow, Naviaux et al continue in their observations on how MIA affected offspring mice and how the administration of suramin seemed to have some pretty wide-ranging effects on offspring mice. Alongside various behavioural effects on social and coordination issues, suramin administration was reported to show important effects such as "the preservation of cerebellar Purkinje cells", which as I discussed in a recent post, have more than a token link to cases of autism. "Suramin treatment strongly increased the expression of the nicotinic acetylcholine receptor subunit α7 (nAchRα7) in cerebral synaptosomes of MIA animals" was another potentially important finding in view of other work in this area. In all, "16 multisystem features of this model were either corrected or improved by suramin treatment".

Impressive stuff I hear you say. Indeed all the more impressive given that the authors on purpose did not start suramin treatment until 6 weeks because they "wished to test the hypothesis that many of the autism-like features of the MIA model were treatable after they appear". And apparently there is more to come according to the authors, with the promise of human trials of suramin...

But just before you pop down to your local doctor or pharmacist to ask for suramin (off-label), it might be worth pointing out a few things. Mice. Yep, this was a study of mice and as per the Schwartzer study, not necessarily the best and only mouse model of autism from an MIA point of view. Indeed if I needed to go back to the BTBR mouse and its overlap with autism, I might also recall some work looking at that most forgotten of autism research parameters, sulphate (sulfate) and findings related to the BTBR model (see here). Mice are not humans and suramin is to be added to a growing list of mouse findings with an autism slant (see here and here).

That the US National Cancer Institute holds an entry for suramin should also give you some idea as to what uses the drug has and why bearing in mind it was injected into the study mice. Alongside its anti-parasitic effects related to things like sleeping sickness, the activity of suramin has been linked to its blocking of various growth factor binding which might yet hold some clue to other effects of the drug outside of competitive inhibiting of purinergic signalling (see here and here). As with most medicines, there are other effects to keep in mind which might also tie into results. And then there are the reported side-effects...

I'm not by any means trying to belittle the Naviaux results of suramin in the MIA mouse model of autism so please do not take this post as such. I am very keen to see some replication studies done in other mouse and other animal models, just to see if the results stack up before progressing to human trials with the all-important focus on 'first do no harm' and whether other meds have similar actions. As such I'll keep my eye open for suramin and autism and perhaps post some updates.

In the meantime, the maternal immune activated hypothesis grinds forward...

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* Schwartzer JJ. et al. Maternal immune activation and strain specific interactions in the development of autism-like behaviors in mice. Translational Psychiatry. 2013; 3: e240.

** Naviaux RK. et al. Antipurinergic therapy corrects the autism-like features in the poly(IC) mouse model. PLoS ONE. 2013; 8: e57380.

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Schwartzer JJ, Careaga M, Onore CE, Rushakoff JA, Berman RF, & Ashwood P (2013). Maternal immune activation and strain specific interactions in the development of autism-like behaviors in mice. Translational psychiatry, 3 PMID: 23481627

Naviaux, R., Zolkipli, Z., Wang, L., Nakayama, T., Naviaux, J., Le, T., Schuchbauer, M., Rogac, M., Tang, Q., Dugan, L., & Powell, S. (2013). Antipurinergic Therapy Corrects the Autism-Like Features in the Poly(IC) Mouse Model PLoS ONE, 8 (3) DOI: 10.1371/journal.pone.0057380

Lipopolysaccharide and autism research

A word that I'm just coming to grips with at the moment forms the subject of this post: lipopolysaccharide, and how LPS is starting to become more and more widely used in research into autism and other developmental / psychiatric conditions. In particular, with reference to some possible involvement from maternal immune activation and risk of various behaviourally-defined conditions in offspring.

What is LPS?

Happy Days @ Wikipedia  

The paper by Raetz & Whitfield* (open-access) provides quite a comprehensive summary of LPS, the hows and whys, but a more concise version goes something like this:

• To use a music analogy, LPS is the cover sleeve for the vinyl album (what's that Grandad?) which is quite a few gram-negative bacteria. 
• LPS is made up of various chemical components; lipid A seems to be an important part of LPS, given that this is the stuff which seems to have quite a lot of the toxicity (endotoxin) effects of gram-negative bacteria attached. One might imagine that with the bacterial connection, those trillions of beasties which inhabit us, or rather our deepest, darkest recesses, might very well produce LPS to some extent.

LPS and immune activation

LPS is turning into quite the immune activation weapon of choice when it comes to animal research on conditions like autism and schizophrenia. Administration of LPS - mimicking gram-negative bacterial infection - is a great way of stimulating the innate immune system as per its effects on macrophage activation (yes, those bigger eaters of the immune system) via the Toll-like receptor 4 (TLR-4) - myeloid differentiation factor 2 (MD-2) complex (see here) and bringing into play all those not-so-lovely pro-inflammatory cytokines. LPS administration also seems to have a few other effects too as per this paper by Suh and colleagues** (open-access) on what happens to various amino acid chemistry when LPS is added. I'm sure there's a lot more also that it does.

With autism research in mind?

Quite a few animals have seen their fair share of LPS in the name of autism and related conditions research with some very interesting observations having been recorded:

• Willette and colleagues*** based on a LPS model of maternal immune activation, found that offspring rhesus monkeys showed more "behavioural disturbance" and brain enlargement when compared with controls. 
• Baharnoori and colleagues**** (open-access) concluded that offspring of LPS immune stimulated mice also showed some interesting changes to dopaminergic chemistry.
• Nouel and colleagues***** reported an effect from prenatal LPS exposure in terms of reduced levels of glutamic acid decarboxylase 67 (GAD67) and reelin in the rat model. Both GAD67 and reelin have been the topic of previous blog posts: GAD in connection to the neurotransmitters glutamate and GABA (see here) and reelin in relation to some interesting research on organophosphates (OPs) (see here).
• Finally, Xu and colleagues****** presented data suggestive that LPS administration might also affect levels of neurotrophin-3 (NT-3), involved in neurogenesis (and not a million miles away from an old favourite, BDNF). 

When applying LPS to media like PBMC provided by people with autism, there have also been some important results:

• Dr Harumi Jyonouchi (a researcher previously discussed on this blog) reported an "excessive innate immune responses in a number of ASD children" following LPS administration in this paper*******. TNF-alpha production (see this post) was of particular interest.
• Further, Dr Jyonouchi and colleagues in this paper******** went on to suggest that the response of adding LPS to PBMCs from participants with autism might also differ as a consequence of whether a gastrointestinal (GI) element was evident alongside autism.

I hope you can see why I'm so interested in LPS as a research tool when it comes to autism. The whole maternal immune activation area of autism research is definitely in the ascendancy as exemplified by the recent inflammation - offspring autism risk paper by Brown and colleagues********* discussed in this post. Indeed for science to even attempt to recreate anything approaching the conditions that *might* be linked to offspring autism with immune function in mind, LPS is a valuable tool alongside other agents such as polyinosinic:polycytidylic acid (poly I:C) highlighted in this paper by Paul Patterson and colleagues********** (open-access).

To finish, how about some Adamski (and Seal)?

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* Raetz CR. & Whitfield C. Lipopolysaccharide endotoxins. Annu Rev Biochem. 2002; 71: 635–700.

** Suh JH. et al. A new metabolomic assay to examine inflammation and redox pathways following LPS challenge. Journal of Inflammation 2012, 9:37

*** Willette AA. et al. Brain enlargement and increased behavioral and cytokine reactivity in infant monkeys following acute prenatal endotoxemia. Behav Brain Res. 2011; 219: 108-115.

**** Baharnoori M. et al. Effect of maternal lipopolysaccharide administration on the development of dopaminergic receptors and transporter in the rat offspring. PLoS One. 2013; 8: e54439.

***** Nouel D. et al. Prenatal exposure to bacterial endotoxin reduces the number of GAD67- and reelin-immunoreactive neurons in the hippocampus of rat offspring. Eur Neuropsychopharmacol. 2012; 22: 300-307.

****** Xu M. et al. Aberrant cerebellar neurotrophin-3 expression induced by lipopolysaccharide exposure during brain development. Cerebellum. January 2013.

******* Jyonouchi H. et al. Proinflammatory and regulatory cytokine production associated with innate and adaptive immune responses in children with autism spectrum disorders and developmental regression. J Neuroimmunol. 2001; 120: 170-179.

******** Jyonouchi H. et al. Dysregulated innate immune responses in young children with autism spectrum disorders: their relationship to gastrointestinal symptoms and dietary intervention. Neuropsychobiology. 2005; 51: 77-85.

********* Brown AS. et al. Elevated maternal C-reactive protein and autism in a national birth cohort. Molecular Psychiatry. January 2013.