Endocannabinoids and fragile X syndrome

Fragile X syndrome (FXS), one of the known causes of autism or rather autistic behaviours, has been receiving quite a lot of research and media attention lately. Arbaclofen (STX209) with FXS in mind was the topic of the most recent post (see here); now we have the article by Kwang-Mook Jung and colleagues* (open-access) on endocannabinoid signalling. There may be quite a few similarities between this latest endocannabinoid research and the growing interest in glutamate and its receptors with FXS in mind, but more on that shortly.

OK let's get it out of the way. Thinking about cannabinoids, I assume some people might initially make the connection back to cannabis and the chief psychoactive substance, delta-9-tetrahydrocannabinol (Δ9-THC), associated with that (in)famous plant. Indeed with the Jung study in mind, it was perhaps inevitable that a headline like: "Cannabis chemical combats chief genetic cause of autism" complete with the necessary picture of a cannabis plant would appear (all that's missing is Bob Marley and some 'herb' music just in case readers required a little more atmosphere).

Suffice to say that the Jung paper focuses on the functioning of the endogenous (endo)cannabinoid system over and above its external chemical relation.

• In particular how in a mouse model, issues with the fragile X mental retardation protein (FMRP) associated with FXS might have some potentially important effects on endocannabinoid signalling by way of metabotropic glutamate receptor-5 (mGluR5) depression. 
• Mention is made of something called 2-arachidonoyl-sn-glycerol (2-AG), a "retrograde endocannabinoid (eCB) transmitter" but other than saying that this is one of the more abundant endocannabinoids seemingly tied into mGluR5 and related to arachidonic acid (AA), I wouldn't pretend to know much more about it. The suggestion is that loss of FMRP has knock-on effects to mGluR5-dependent release of of 2-AG.
• Aside from the basic science of endocannabinoid signalling in said mouse model of FXS, a particularly interesting part of the Jung study is the suggestion of pharmacological 'rescuing' of 2-AG signalling and the subsequent positive impact on some of the mouse subjects displayed behaviours. 
• The pharmacological agent in question was something called JZL184, an inhibitor of the enzyme which usually degrades 2-AG (monoglycerol lipase, MGL) bearing in mind that said inhibition was irreversible. 

Hopefully I've got the main features of the study and its findings right and not confused you with all the terminology. Jung et al including Daniele Piomelli are no strangers to research on the endocannabinoid system and glutamatergic signalling as per papers like this one (full-text) and this one (full-text).

There are a few very obvious caveats to this latest work; not least that mice were the lucky participants and questions on those all-important extrapolations from mice findings to human findings which still need much greater investigation outside of the range of mouse models available to autism research. Emphasising also that this was a study of fragile X syndrome and the mutations associated with this autism-presenting condition, which may not be directly transferable to the range of other non-FXS autisms.

Having said all that I'm interested in this work for a few other reasons. As mentioned earlier on, fragile X syndrome and its relationship with glutamate and glutamate signalling is fast becoming a hot topic. If I were a betting man, I'd probably put a few quid/bucks/euro on a long-shot for glutamate and its receptors turning up as a commonality in quite a few behaviourally-defined conditions. Not necessarily as a core 'reason' but an important factor nonetheless.

I note also that MGL-inhibitors such as JZL184 have been discussed with concepts like protection from neuroinflammation (as a consequence of altering prostaglandin production) in mind** and indeed with another interesting topic in mind, intestinal permeability as per this study by Alhamoruni and colleagues***. All that outside of the possible inflammatory bowel disease link**** (open-access) too. On the basis of these and other research, I'm wondering about the centrality and specificity of the brain to any effects and indeed whether maintaining 2-AG levels may also be affecting other organs as part and parcel of any therapeutic, or indeed non-therapeutic, effect.

Enough with all this science and stuff. Ladies and gentlemen, welcome to paradise...

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* Jung KM. et al. Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome. Nature Communications. 2012; 3: 1080. PMID: 23011134

** Nomura DK. et al. Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science. 2011; 334: 809-813.

*** Alhamoruni A. et al. Cannabinoids mediate opposing effects on inflammation-induced intestinal permeability. British Journal of Pharmcology. 2012; 165: 2598-2610.

**** Alhouayek M. et al. Increasing endogenous 2-arachidonoylglycerol levels counteracts colitis and related systemic inflammation. FASEB J. 2011; 25: 2711-2712.

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Kwang-Mook Jung, Marja Sepers, Christopher M. Henstridge, Olivier Lassalle, Daniela Neuhofer, Henry Martin, Melanie Ginger, Andreas Frick, Nicholas V. DiPatrizio, Ken Mackie, Istvan Katona, Daniele Piomelli, & Olivier J. Manzoni (2012). Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome Nature Communications, 3 DOI: 10.1038/ncomms2045