Advances in modern genetics are rapidly changing the way we approach autism spectrum disorder (ASD) and other complex brain disorders. For example, massive sequencing efforts have identified over 50 ‘high confidence’ genes that possess intrinsic diagnostic and predictive value for ASD (De Rubeis et al, 2014; Iossifov et al, 2014). A post hoc analysis reveals that these genes encode protein products that are primarily localized to post-synaptic boutons and are involved in synthesis of synaptic proteins. Preclinical studies have begun to stratify syndromic forms of autism into groups defined by varying degrees of excitatory/inhibitory imbalance. Importantly, the phenotypic overlap among these disorders has provided optimism that viable therapeutics might emerge that show efficacy in both monogenetic and idiopathic ASD populations due to similarly disrupted signaling pathways.

Perhaps the most well studied potential therapeutic mechanism is that of metabotropic glutamate receptor 5 (mGlu5) antagonism in fragile X syndrome (FXS), where genetic and pharmacological strategies of reducing mGlu5-dependent protein synthesis have shown robust preclinical efficacy. However, the failure of two phase 2 clinical trials has caused many to question whether the target is viable (Jacquemont et al, 2014). An alternative approach is use of the GABAB receptor agonist arbaclofen, which normalizes excessive protein synthesis and excitatory/inhibitory imbalance in FXS model mice. While a phase 2b clinical trial failed to achieve its primary endpoint of treating irritability, post hoc analysis with the Aberrant Behavior Checklist -Social Avoidance scale, a recently validated scale for the assessment of FXS, showed a treatment effect in the full study population. A post hoc subgroup of 27 subjects with more severe social impairment also showed improvements on the Vineland II socialization raw scores and on the Aberrant Behavior Checklist-Social Avoidance scale (Jacquemont et al, 2014).

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