Friday, 29 June 2012

The BTBR mouse and autism

Danger Mouse (from Wikipedia)
It is slightly overwhelming to see the wide range of investigative and research techniques on offer to the modern day scientist when it comes to researching conditions like autism. Indeed, the variety of disciplines and the tools of their trade involved in looking at autism from almost every conceivable research angle, makes it all the more difficult to understand why, at the time of writing, we continue to know so little about autism - aetiology, underlying pathology, etc. - despite such intensive efforts. I'm not here to answer that question by the way; aside that is from mentioning about heterogeneity, comorbidity, genetics-epigentics-environment and the well-trodden path that is 'if you've met one person with autism, you've met one person with autism'.

As per many other conditions / diseases / states, autism research has more than dabbled in the science of trying to establish suitable animal models for the condition as per this review by Paul Patterson* who runs quite a good blog (here). Without wishing to enter into any moral or ethical arguments with anyone about it, quite a few mice, rats, zebrafish and other creatures have met their Maker over the years in the name of autism research. Suffice to say that many more animals are probably going to join them in future; at least more than those who would have been involved in cosmetic research now the European Cosmetics Directive comes into final force (March 2013).

Animal models survive however because of the perceived comparison they can provide where investigations on human beings would not dare to tread. So, inserting genes, deleting genes, controlled exposure to various chemical and drug residues, and lots of other investigations all figure in autism animal research; studies which would not even be entertained to be involving real human beings. The big question though is: how much do such animal models truly tell us about a complex and heterogeneous condition like autism?

Bearing that question in mind, there is one particular animal model of autism which seems to be part of quite a few studies: the BTBR mouse or to give it the full title: the BTBR T+tf/J inbred mouse strain. I should add that I was brought to doing this entry partly following this post on the SFARI website.

Aside from being described as an 'exceptional breeder'(!), the BTBR mouse is of potential interest to autism research because it 'seems' to share quite a few overt behaviours more usually associated with autism spectrum conditions such those involved in social interaction, repetitive behaviours and impairments in play behaviour (see this paper). Even communication by the BTBR mouse has been suggested to some degree, to mirror that seen in autism (here). Throw in indications of 'high anxiety' and it all makes for an attractive animal model of autism.

So what has been noted about this mouse:

With the weight of this evidence you can perhaps see why the BTBR mouse might find some favour as a model of autism. There seems to be something for every research palate in among the various studies of the BTBR mouse. I'm certainly not going to poo-poo any comparisons but do have a few minor points to make aside from those already mentioned.

I am genuinely interested in what you might use as a comparator in mouse terms to the BTBR model. Most human studies around autism, certainly interventional or parameter-based, tend to use an asymptomatic control group (hopefully age- and sex-matched) or if you are very lucky, a further group of people with conditions like learning disability or a speech and language disorder (without autism) or the equivalent as comparators. I might be missing important details here but what do you compare an 'autistic mouse' with when ascertaining a specific biological or genetic parameter? Is there such a thing as an 'asymptomatic' mouse or a mouse with learning disability for example or is autism a spectrum of presentation in mice too? (no cheap jokes about systemising mice please).

A further point relates to the something that has cropped up on previous posts in terms of lab mice vs. wild mice and in particular the effects of environment on each as per this article by Boysen and colleagues*******. To quote: "These findings indicate a high degree of pre-activation of NK cells of free-living mice, indicating a strong environmental impact on NK cells, which may be highly relevant for interpretation of studies in the mouse model". In other words, lab mice in their nice sterile, clean-living, environment might not be hardened by the cruel outside world and therefore one questions their representativeness to the real world.

Indeed whilst animal models of 'disease' are the backbone of many a genetic or biological study, there are still some questions about whether they are truly delivering what they promised in terms of translating from lab bench to real-life as per the paper by van der Worp and colleagues******** (full-text) from a few years back. If this is the case, where does this leave the BTBR mouse?

[The picture included in this post will be recognisable to quite a few 'older kids' raised on 1980s UK television. For those who have not had the pleasure of watching Danger Mouse and his sidekick Penfold, here's some more information and that theme tune].


* Patterson PH. Modelling autistic features in animals. Pediatric Research. 2011; 69: 34R-40R

** Silverman JL. et al. Repetitive self-grooming behavior in the BTBR mouse model of autism is blocked by the mGluR5 antagonist MPEP. Neuropsychopharmacology. 2010; 35: 976-989.

*** Frye CA. & Llaneza DC. Corticosteroid and neurosteroid dysregulation in an animal model of autism, BTBR mice. Physiology & Behaviour. 2010; 100: 264-267.

**** Mercier F. et al. Meningeal/vascular alterations and loss of extracellular matrix in the neurogenic zone of adult BTBR T+ tf/J mice, animal model for autism. Neuroscience Letters. 2011; 498: 173-178.

***** Heo Y. et al. Aberrant immune responses in a mouse with behavioral disorders. PLoS One. 2011; 6: e20912

****** Corley MJ. et al.Reduced sulfate plasma concentrations in the BTBR T+tf/J mouse model of autism. Physiology & Behaviour. April 2012.

******* Boysen P. et al. Natural killer cells in free-living Mus musculus have a primed phenotype. Molecular Ecology. 2011; 20: 5103-5110.

******** van der Worp HB. et al. Can animal models of disease reliably inform human studies? PLoS Medicine. 2010;  7: e1000245.