The most commonly inherited form of autism involves the gene encoding fragile X mental retardation protein (FMRP). Loss of FMRP function disrupts signaling between neurons, leading to widespread brain abnormalities and mental retardation. Normally, FMRP is balanced by mGluR5, an important receptor in the brain that is involved in learning and memory. Without normal FMRP, this balance is lost, leaving mGluR5 function unopposed. Early results from a clinical trial suggest that children with fragile X syndrome can be helped by drugs that inhibit mGluR5 activity. Karen O'Malley and her colleagues have shown that up to 90 percent of mGluR5 receptors are found inside neurons, where they can regulate different signaling systems. Stimulation of this mGluR5 induces long, sustained calcium increases, leading to the modification of proteins involved in learning and memory. In contrast, mGluR5 stimulation on the outside of the neuron triggers rapid, transient calcium signals. Most studies so far have used drugs that cannot enter the cell. O'Malley and colleagues aim to re-examine mGluR5 pathways using molecules that specifically activate the intracellular receptors. Using pharmacological, molecular and genetic tools, O'Malley and colleagues plan to test whether intracellular mGluR5 responses underlie fundamental properties of learning and memory, such as protein synthesis, increased FMRP, and increased branching of neurons. These properties will also be examined in animals lacking mGluR5 and FMRP. Given its role in fragile X syndrome and autism, mGluR5 makes an attractive target for drug discovery. Future studies targeting drugs specifically to the cell surface or to intracellular receptors might lead to new therapeutic tools for fragile X and autism.