A study published in Proceedings of the National Academy of Sciences of the USA provides evidence that the fragile X mental retardation protein (FMRP) might be involved in the translational regulation of synaptic proteins. Mutations in FMR1, which encodes FMRP, cause fragile X syndrome, one of the most common causes of mental retardation.

Although FMRP has been implicated in translational regulation, and is known to bind to many messenger RNAs that are found in the brain (including its own), its functions are far from clear. The new study, by Todd and colleagues, shows that levels of FMRP are increased in primary cortical neurons that are treated with a metabotropic glutamate receptor (mGluR) agonist. This rise is accompanied by an increase in the translation of PSD95, a scaffolding protein that is important for synaptic assembly. Both of these effects can be prevented by treatment with an mGluR antagonist, and the rise in PSD95 is not seen in cultures derived from mice that lack FMRP.

The mRNA for PSD-95 contains a so-called 'G-quartet' sequence, which is found in other mRNAs that are bound by FMRP. The evidence indicates that activation of mGluRs causes translation of FMRP to be increased, and that this acts on the mRNA of PSD95 to increase its translation. Surprisingly, neither treatment of the neurons with glutamate nor depolarization with KCl leads to upregulation of FMRP or PSD95. This indicates that the context in which mGluR receptors are activated is important for these effects.

Although FMRP is known to bind to many other mRNAs, and therefore is likely to influence translation of a wide range of proteins, these results raise the possibility that some of the neuropathology of fragile X syndrome might result from abnormal regulation of PSD95 expression, which could alter mGluR-dependent synaptic plasticity. Further work will need to define how mGluR activation upregulates FMRP translation, and which other proteins are regulated in this way.