**4. Toward a treatment?**

Ultimately, the primary goal of genome research should be to propose targets for interven‐ tion. As mentioned above, a number of translational studies have begun to probe the metab‐ otropic glutamate receptor, mGluR5, as a potential target for fragile X syndrome treatment. These studies have a theoretical basis in the hypothesis that protein-synthesis-dependent functions of metabotropic receptors are exaggerated in fragile X syndrome (Bear, Huber & Warren, 2004) [87]. Thus, the fragile X protein, FMRP, is thought to work in functional oppo‐ sition to mGluR5 (and mGluR1). Where FMRP is absent, mGluR-dependent protein synthe‐ sis becomes over-activated, resulting in neurological and behavioral abnormalities.

Dölen *et al*. (2007) [89] crossed *Fmr1* mutant with Grm5 mutant to produce *Fmr1* knockouts who also had a selective reduction in mGluR5 expression. They found that a 50% reduction in mGluR5 gene dosage rescued a range of deficits in *Fmr1* mutants. Relevant measures in‐ cluded protein synthesis in hippocampus, density of dendritic spines (layer 3 pyramidal neurons), visual responsiveness, and cognitive performance (inhibitory avoidance – a hippo‐ campus-dependent memory). This provides confirmation that mGluR5 and FMRP are func‐ tionally oppositional. Moreover, it suggests possible pharmacological avenues by which this genetic disease may be treated.

A range of translational studies have begun to target this pathway. These include efforts to inhibit the activity of individual mGluR5 (Jacquemont *et al*., 2011; Berry-Kravis *et al*., 2009) [88,90], and FMRP-regulated proteins (Paribello *et al*., 2010) [91], NMDA (Wei *et al*., 2012) [92], and GSK3β (lithium, Berry-Kravis *et al*., 2008) [93], which have shown promise in open label and (in some instances) clinical trials (see Berry-Kravis *et al*., 2011 for review) [94]. Moreover, these compounds may have clinical application to the broader ASD phenotype. Silverman *et al*. (2012) [95] recently reported that the mGluR5 antagonist, GRN-529, de‐ creased ASD-related symptoms of autism in two different mouse models of the disease (re‐ petitive grooming/repetitive jumping). In addition to the Iossifov *et al*. (2012) [85] sequencing study discussed above, Kelleher *et al*. (2012) [96] recently showed that idiopathic autism cases may have higher burden of mGluR5 variants. The group found that in 209 idio‐ pathic cases, there was significant enrichment for rare functional variants in the mGluR5 pathway—namely the genes *TSC1*, *TSC2* and *SHANK3*, and *HOMER1*—relative to controls (n=300). It is likely that drugs targeting the mGluR5 pathway, if/when approved for fragile X syndrome, will lead to human clinical trials for ASD. This translational approach – which delineates a direct route from gene discovery, through functional validation to treatment, is clearly the blueprint by which genome research can have tangible clinical impact.
