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

doi:10.1073/pnas.2336265100

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

Departments of ^*Pathology and ^§Neurology, ^†Neuroscience Training Program, and ^‡Waisman Center for Developmental Disabilities, University of Wisconsin, 1500 Highland Avenue, Madison, WI 53705

Communicated by William T. Greenough, University of Illinois at Urbana-Champaign, Urbana, IL, September 29, 2003 (received for review July 31, 2002)

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.

Footnotes

↵ ∥ To whom correspondence should be addressed at: T509, Waisman Center for Developmental Disabilities, 1500 Highland Avenue, University of Wisconsin, Madison, WI 53705. E-mail: jsmalter{at}facstaff.wisc.edu.
↵ ¶ Present address: Department of Child and Adolescent Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.
Abbreviations: FMRP, fragile X mental retardation protein; mGluR, metabotropic glutamate receptor; DHPG, S-3,5-dihydrophenylglycine; PHCCC, N-phenyl-7-(hydroxyimino)cyclopropachromen-1α-carboxamide; KO, knockout.