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.