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The Journal of Neuroscience, November 7, 2007, 27(45):12378-12389; doi:10.1523/JNEUROSCI.2970-07.2007

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Neurobiology of Disease
Drosophila Fragile X Mental Retardation Protein and Metabotropic Glutamate Receptor A Convergently Regulate the Synaptic Ratio of Ionotropic Glutamate Receptor Subclasses

Luyuan Pan and Kendal S. Broadie

Department of Biological Sciences, Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee 37232

Correspondence should be addressed to Prof. Kendal S. Broadie, 6270 MRB III, 465 21st Avenue South, Nashville, TN 37232. Email: kendal.broadie{at}vanderbilt.edu

A current hypothesis proposes that fragile X mental retardation protein (FMRP), an RNA-binding translational regulator, acts downstream of glutamatergic transmission, via metabotropic glutamate receptor (mGluR) G_q-dependent signaling, to modulate protein synthesis critical for trafficking ionotropic glutamate receptors (iGluRs) at synapses. However, direct evidence linking FMRP and mGluR function with iGluR synaptic expression is limited. In this study, we use the Drosophila fragile X model to test this hypothesis at the well characterized glutamatergic neuromuscular junction (NMJ). Two iGluR classes reside at this synapse, each containing common GluRIIC (III), IID and IIE subunits, and variable GluRIIA (A-class) or GluRIIB (B-class) subunits. In Drosophila fragile X mental retardation 1 (dfmr1) null mutants, A-class GluRs accumulate and B-class GluRs are lost, whereas total GluR levels do not change, resulting in a striking change in GluR subclass ratio at individual synapses. The sole Drosophila mGluR, DmGluRA, is also expressed at the NMJ. In dmGluRA null mutants, both iGluR classes increase, resulting in an increase in total synaptic GluR content at individual synapses. Targeted postsynaptic dmGluRA overexpression causes the exact opposite GluR phenotype to the dfmr1 null, confirming postsynaptic GluR subtype-specific regulation. In dfmr1; dmGluRA double null mutants, there is an additive increase in A-class GluRs, and a similar additive impact on B-class GluRs, toward normal levels in the double mutants. These results show that both dFMRP and DmGluRA differentially regulate the abundance of different GluR subclasses in a convergent mechanism within individual postsynaptic domains.

Key words: mental retardation; fragile X syndrome; protein synthesis; synapse; postsynaptic; metabotropic glutamate receptor; synaptic plasticity

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Received Feb. 14, 2007; revised Sept. 15, 2007; accepted Sept. 22, 2007.

Correspondence should be addressed to Prof. Kendal S. Broadie, 6270 MRB III, 465 21st Avenue South, Nashville, TN 37232. Email: kendal.broadie{at}vanderbilt.edu

This article has been cited by other articles:

				L.-F. Qiu, T.-J. Lu, X.-L. Hu, Y.-H. Yi, W.-P. Liao, and Z.-Q. Xiong Limbic Epileptogenesis in a Mouse Model of Fragile X Syndrome Cereb Cortex, October 1, 2008; (2008) bhn163v1. [Abstract] [Full Text] [PDF]

				C. L. Gatto and K. Broadie Temporal requirements of the fragile X mental retardation protein in the regulation of synaptic structure Development, August 1, 2008; 135(15): 2637 - 2648. [Abstract] [Full Text] [PDF]

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