|Danger Mouse (from Wikipedia)|
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:
- Silverman and colleagues** reported that administration of 2-Methyl-6-(phenylethynyl)pyridine (MPEP), an antagonist for the metabotropic glutamate receptor subtype mGluR5, seemed to reduce the instance of repetitive (self-grooming) behaviour in BTBR mice. Regular readers to this blog might remember my post on glutamate (and glutamine) and autism and some news not so long about about GRN-529 and autism which caused a bit of a stir.
- Frye & Llaneza*** reported on elevations in circulating and brain levels of the neurosteroid, 5α-pregnan-3α-ol-20-one (3α,5α-THP) - a metabolite of progesterone - in the BTBR mouse. The endocrine system has shown more than a passing relationship to cases of autism; be it through the hypothalamus (dopamine, oxytocin, vasopressin) or the link posited between autism and sex hormones (see recent post on PCOS and autism). Dare I even make mention of endocrine disruptors?
- Mercier and colleagues**** indicated the potential presence of connective tissue issues (?) when looking at the anatomy of the meninges in the BTBR mouse. Putting aside my obsession with leaky barriers and autism (and other conditions) and appreciating the difference between the meninges and the blood-brain barrier, I can't help but wonder...
- Heo and colleagues***** reported on elevated levels of anti-brain antibodies amongst other things in relation to immune function of the BTBR mouse. To quote from the authors: "The Th2-like immune profile of the BTBR mice and their constitutive neuroinflammation suggests that an autoimmune profile is implicated in their aberrant behaviors". Inflammation... say no more.
- Finally, I've already talked about the paper by Corley and colleagues****** and their findings of low plasma sulphate (sulfate) in the BTBR mouse (see here) so won't say too much more now.
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.