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The Journal of Neuroscience, May 16, 2007, 27(20):5338-5348; doi:10.1523/JNEUROSCI.0937-07.2007

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Cellular/Molecular
Dysregulated Metabotropic Glutamate Receptor-Dependent Translation of AMPA Receptor and Postsynaptic Density-95 mRNAs at Synapses in a Mouse Model of Fragile X Syndrome

Ravi S. Muddashetty,^1 * Sofija Keli,^3 * Christina Gross,¹ Mei Xu,² and Gary J. Bassell^1,2

¹Departments of Cell Biology and ²Neurology, Emory University, Atlanta, Georgia 30322, and ³Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York 10461

Correspondence should be addressed to either of the following: Gary J. Bassell, Department of Cell Biology, Emory University, 615 Michael Street, Atlanta, GA 30322, Email: gbassel{at}emory.edu; or Sofija Kelic at her present address, Hoffman-La Roche, 340 Kingsland Street, Nutley, NJ 07110, Email: sofija.kelic{at}roche.com

Fragile X syndrome, a common form of inherited mental retardation, is caused by the loss of fragile X mental retardation protein (FMRP), an mRNA binding protein that is hypothesized to regulate local mRNA translation in dendrites downstream of gp1 metabotropic glutamate receptors (mGluRs). However, specific FMRP-associated mRNAs that localize to dendrites in vivo and show altered mGluR-dependent translation at synapses of Fmr1 knock-out mice are unknown so far. Using fluorescence in situ hybridization, we discovered that GluR1/2 and postsynaptic density-95 (PSD-95) mRNAs are localized to dendrites of cortical and hippocampal neurons in vivo. Quantitative analyses of their dendritic mRNA levels in cultured neurons and synaptoneurosomes did not detect differences between wild-type and Fmr1 knock-out (KO) mice. In contrast, PSD-95, GluR1/2, and calcium/calmodulin-dependent kinase II (CaMKII) mRNA levels in actively translating polyribosomes were dysregulated in synaptoneurosomes from Fmr1 knock-out mice in response to mGluR activation. [³⁵S]methionine incorporation into newly synthesized proteins similarly revealed impaired stimulus-induced protein synthesis of CaMKII and PSD-95 in synaptoneurosomes from Fmr1 KO mice. Quantitative analysis of mRNA levels in FMRP-specific immunoprecipitations from synaptoneurosomes demonstrated the association of FMRP with CaMKII, PSD-95, and GluR1/2 mRNAs. These findings suggest a novel mechanism whereby FMRP regulates the local synthesis AMPA receptor (AMPAR) subunits, PSD-95, and CaMKII downstream of mGluR-activation. Dysregulation of local translation of AMPAR and associated factors at synapses may impair control of the molecular composition of the postsynaptic density and consequently alter synaptic transmission, causing impairments of neuronal plasticity observed in Fmr1 knock-out mice and fragile X syndrome.

Key words: fragile X syndrome; fragile X mental retardation protein; local protein synthesis; synaptoneurosomes; dendritic mRNA localization; AMPA receptor; postsynaptic density-95

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Received Aug. 15, 2005; revised April 3, 2007; accepted April 6, 2007.

Correspondence should be addressed to either of the following: Gary J. Bassell, Department of Cell Biology, Emory University, 615 Michael Street, Atlanta, GA 30322, Email: gbassel{at}emory.edu; or Sofija Kelic at her present address, Hoffman-La Roche, 340 Kingsland Street, Nutley, NJ 07110, Email: sofija.kelic{at}roche.com

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