Npgrj_nchembio_78 256..263

Fragile X syndrome is caused by the functional loss of the fragile X mental retardation 1 (FMR1) gene. D eletion of the FMR1 ortholog in D rosophila melanogaster (Fmr1) recapitulates many phenotypes associated w ith fragile X syndrome. W e have discovered that Fmr1 mutant D rosophila die during development when reared on food containing increased levels of glutamate, w hich is consistent w ith the theory that FMR1 loss results in excess glutamate signaling. U sing this lethal phenotype, w e screened a chemical library of 2,000 compounds and identi fied nine molecules that rescued the lethality, including three that implicate the G AB Aergic inhibitory pathway. Indeed, G ABA treatment rescued several known Fmr1 mutant phenotypes in fl ies, including mushroom bodies defects, excess Futsch translation and abnormal male courtship behavior. These data are consistent w ith G AB Aergic inhibition of the enhanced excitatory pathw ay in fragile X syndrome. In addition, our screen reveals that the muscarinic cholinergic receptors may have a role in fragile X syndrome in parallel to the G AB Aergic path way. These results point to potential therapeutic approaches for treating fragile X syndrome.