i o t r h m o O nly a decade ago, it was believed that a genetic diagnosis of intellectual disability and autism offered little in the way of hope for a medical treatment to lessen the burden on the ffected individuals and their families. However, recent research imed at understanding the cellular and molecular mechanisms hat underlie the pathogenesis of ASD has ushered in a new era of argeted treatment strategies. Studies in fragile X syndrome (FXS) ave been at the forefront of this revolution, and they are forging a ath that could define future approaches to the treatment of ASD. FXS is the leading identified genetic cause of autism. Because it s a defined genetic disorder that can be effectively modeled in nimals, the study of FXS has great potential to yield information bout the pathophysiology of ASD. FXS is caused by a silencing of he FMR1 gene and the loss of fragile X mental retardation protein FMRP), a repressor of mRNA translation. Early studies suggested hat synaptic protein synthesis is stimulated by activation of group (Gp1) metabotropic glutamate receptors (comprising mGluR1 nd mGluR5) and that one functional consequence of this protein ynthesis is the long-term depression (LTD) of synaptic strength reviewed in in Bhakar et al. [1]). The subsequent discovery that LTD s elevated in the mouse model of FXS (Fmr1 ) led to the proposal hat multiple symptoms of the disease might be accounted for by eightened responsiveness to Gp1 mGluR activation. This mGluR heory of fragile X predicted that the antagonism of Gp1 mGluRs hould correct pathologic changes in FXS (2). In the decade that lapsed since it was first proposed, numerous studies in a range of nimal models have validated this theory. The animal data show hat many aspects of FXS can be accounted for by altered Gp1 GluR signaling at synapses. This insight is the basis for multiple linical trials that are now underway in FXS (for extensive reviews ee Bhakar et al. [1] and Krueger and Bear [3]). The first clinical test of the mGluR theory was a small, open-label rial using fenobam, a Gp1 mGluR antagonist that is highly selective or mGluR5. The results of this small trial showed beneficial effects n a subset of the adult FXS patients tested; however, it is important o note that no placebo control group was included in this trial, nor as it performed in an experimenter blind fashion (4). Since this nitial study, multiple large-scale placebo-controlled trials have been nitiated with selective mGluR5 negative allosteric modulators— amely, STX107 (Seaside Therapeutics, Cambridge, Massachusetts), G7090 (Hoffman-LaRoche, Basel, Switzerland), and AFQ056 (Novartis, asel, Switzerland). Although the results of most of these trials have yet o be revealed, in post hoc analysis of Phase II data AFQ056 was reorted to show an improvement on multiple behavioral tests in adult atients with a fully methylated (silenced) FMR1 gene. In tandem with drugs that directly interfere with mGluR5, other rugs that may indirectly target Gp1 mGluR signaling are also being ested in clinical trials. One strategy for reducing mGluR activation is