Fragile X syndrome (FXS) is caused by expansion of a CGG triplet repeat in the FMR1 gene (gene product FMRP), leading to transcriptional silencing of FMR1 and deficiency of FMRP, which results in deregulated synaptic protein synthesis, deficiencies in GABA-mediated inhibitory neurotransmission and exaggerated responses to metabotropic glutamate receptors (mGluRs) that underlie cognitive and behavioral deficits in FXS patients. As GABA receptors inhibit glutamate release, Henderson et al. tested whether GABA receptor activation could indirectly reduce postsynaptic mGluR activation and ameliorate the physiological and behavioral defects in the Fmr1 knockout mouse model. They found that the GABAB receptor agonist STX209 reduced synaptic protein synthesis and other molecular defects from Fmr1 deficiency, perhaps by affecting translation of the FMRP targets. STX209 also reduced seizure incidence and repetitive behavior in the mice and restored normal spine density of pyramidal neurons from the binocular visual cortex, a correction of the pruning and shaping defects of the neuronal network that underlie FXS. In a parallel study, Berry-Kravis et al. tested the effects of STX209 on one of the core phenotypes of human FXS, the social impairment that is thought to be due to exaggerated responses to mGluRs. In a post hoc analysis, the authors saw improvements in social avoidance, consistent with a model where social impairments in FXS are related to GABA deficiencies or exaggerated glutamatergic signaling. These studies add STX209 to the repertoire of potential FXS drug leads, such as agents that modulate mGluR receptors directly.
Rights and permissions
About this article
Cite this article
Bucci, M. Fixing fragility. Nat Chem Biol 8, 872 (2012). https://doi.org/10.1038/nchembio.1100
Published:
Issue Date:
DOI: https://doi.org/10.1038/nchembio.1100
