The fragile X mental retardation protein is required for type-I metabotropic glutamate receptor-dependent translation of PSD-95

Peter K. Todd, Kenneth J. Mack, James S. Malter

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Abstract

Fragile X syndrome (FXS) is a common inherited cause of mental retardation resulting from the absence of the fragile X mental retardation protein (FMRP). FMRP is thought to regulate the translation of target mRNAs, including its own transcript. Here we show that the levels of FMRP are rapidly up-regulated in primary cortical neurons in response to the type-I metabotropic glutamate receptor (mGluR) agonist S-3,5-dihydrophenylglycine. These changes require new protein synthesis but not transcription and are specific to mGluR activation. We also demonstrate that the mRNA for PSD-95, a scaffolding protein involved in synaptic plasticity, contains a highly conserved canonical binding site for FMRP within its 3′ UTR. Furthermore, PSD-95 is rapidly translated in response to S-3,5-dihydrophenylglycine. Finally, we show that these mGluR-dependent changes in PSD-95 expression are lost in neurons derived from FMRP knockout mice, a model of FXS. Taken together, these studies suggest that FMRP is required for mGluR-dependent translation of PSD-95 and provide insights into the pathophysiology of FXS.

Original languageEnglish (US)
Pages (from-to)14374-14378
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue numberSUPPL. 2
DOIs
StatePublished - Nov 25 2003

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