title: Astroglial FMRP-dependent translational down-regulation of mGluR5 underlies glutamate transporter GLT1 dysregulation in the fragile X mouse.
abstract: Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the loss-of-function of fragile X mental retardation protein (FMRP). The loss of FMRP function in neurons abolishes its suppression on mGluR1/5-dependent dendritic protein translation, enhancing mGluR1/5-dependent synaptic plasticity and other disease phenotypes in FXS. In this study, we describe a new activation function of FMRP in regulating protein expression in astroglial cells. We found that astroglial glutamate transporter subtype glutamate transporter 1 (GLT1) and glutamate uptake is significantly reduced in the cortex of fmr1(-/-) mice. Correspondingly, neuronal excitability is also enhanced in acute fmr1(-/-) (but not in fmr1(+/+) control) cortical slices treated with low doses (10 μm) of the GLT1-specific inhibitor dihydrokainate (DHK). Using mismatched astrocyte and neuron co-cultures, we demonstrate that the loss of astroglial (but not neuronal) FMRP particularly reduces neuron-dependent GLT1 expression and glutamate uptake in co-cultures. Interestingly, protein (but not mRNA) expression and the (S)-3,5-dihydroxyphenylglycine-dependent Ca(2+) responses of astroglial mGluR5 receptor are also selectively reduced in fmr1(-/-) astrocytes and brain slices, attenuating neuron-dependent GLT1 expression. Subsequent FMRP immunoprecipitation and QRT-PCR analysis showed that astroglial mGluR5 (but not GLT1) mRNA is associated with FMRP. In summary, our results provide evidence that FMRP positively regulates translational expression of mGluR5 in astroglial cells, and FMRP-dependent down-regulation of mGluR5 underlies GLT1 dysregulation in fmr1(-/-) astrocytes. The dysregulation of GLT1 and reduced glutamate uptake may potentially contribute to enhanced neuronal excitability observed in the mouse model of FXS.
authors: Department of Neuroscience, Tufts University School of Medicine, 136 Harrison Ave, Boston, MA 02111, USA.
authors: Haruki
authors: H
authors: Higashimori
authors: Lydie
authors: L
authors: Morel
authors: James
authors: J
authors: Huth
authors: Lothar
authors: L
authors: Lindemann
authors: Chris
authors: C
authors: Dulla
authors: Amaro
authors: A
authors: Taylor
authors: Mike
authors: M
authors: Freeman
authors: Yongjie
authors: Y
authors: Yang
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation; D027342:Excitatory Amino Acid Transporter 2 / Q000096:biosynthesis* / Q000235:genetics; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D055785:Gene Knockdown Techniques; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007608:Kainic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000378:metabolism; D014176:Protein Biosynthesis; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*
chemical_list: D027342:Excitatory Amino Acid Transporter 2; D051860:Fragile X Messenger Ribonucleoprotein 1; D018698:Glutamic Acid; D007608:Kainic Acid; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C497684:Fmr1 protein, mouse; C578935:GRM5 protein, human; C578936:Grm5 protein, mouse; C493396:Slc1a2 protein, mouse; C020889:dihydrokainic acid
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