The hyposerotonemic mouse and autism

Dear readers, please don't be put of this post by the title. All it refers to is a mouse described by Kane and colleagues* (open-access) which was engineered with a null mutation in the TPH2 gene governing the production of tryptophan hydroxylase, a required step in the synthesis of the aromatic amino acid tryptophan to everyone's favourite neurotransmitter, serotonin (or as we Brits like to call it 5-HT). Said mouse was unable to produce serotonin and hence lacked it - hyposerotonemia - despite having all the necessary receptors et al.

Meeces to pieces... @ Wikipedia  

Kane and colleagues set about looking at mice "derived from matings of heterozygous (TPH2+/−) males and heterozygous (TPH2+/−) females on a mixed C57BL/6-Sv129 background".

This selective breeding produced offspring who were homozygous for the null mutation, basically carrying the null mutation on both chromosome pairs (TPH2-/-). They then set about testing the TPH2-/- mice on various measures across various ages corresponding to human years (infancy, juvenile, adulthood) and compared results with wild-type pups who were not serotonin deficient.

Their findings? Well, the TPH2-/- mice presented with some interesting developmental features. A delay in hitting certain developmental milestones, transient early brain overgrowth normalising into the equivalent teen years and adulthood, among other things.

When put to various tasks equivalent to looking at some of the core and peripheral features associated with human autism spectrum disorders - a kind of mouse ADOS if you will - the TPH2-/- mice showed some significant differences in their behaviours compared with wild-type mice. So less preference for mother mouse's scent interpreted as the "early signs of a social communication deficit", alongside other socialisation issues and lots of repetitive, compulsive behaviours persisting into mouse adulthood. I'm not going to get to heavily into each individual finding because it's all there in the full-text paper.

The authors conclude: "these results indicate that a hypo-serotonin condition can lead to behavioral traits that are highly characteristic of autism" and certainly I am not going to disagree with them. Yes, you could again use the argument that this was a mouse and not a human being, and the fact us humans are very, very, very complicated creatures by comparison. You could also argue that quite a few of the behaviours described by Kane and colleagues are also associated with other behavioural and psychiatrically-defined conditions and need not be just necessarily construed as autism; depression for example, bearing in mind the timing of presentation. It's a complicated picture of inference and 'ifs and buts' not helped by the mixed bag of research on serotonin and autism.

I remain however interested in these findings and indeed in the whole area of mouse models and autism given previous discussions on the BTBR dangermouse and also how mouse models might be able to translate autism hypotheses into viable murine-based findings. Er, should I mention sulphation and leaky gut here too, or is that old news now? Bearing in mind that those TPH2-/- mice might also carry other mutations and indeed epigenetic differences too, I'll be keeping an eye on the hyposerotonemic mouse research and just how useful it might be to autism research.

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* Kane MJ. et al. Mice genetically depleted of brain serotonin display social impairments, communication deficits and repetitive behaviors: possible relevance to autism. PLoS ONE. 2012; 7: e48975.

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Kane MJ, Angoa-Peréz M, Briggs DI, Sykes CE, Francescutti DM, Rosenberg DR, & Kuhn DM (2012). Mice genetically depleted of brain serotonin display social impairments, communication deficits and repetitive behaviors: possible relevance to autism. PloS one, 7 (11) PMID: 23139830