Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice
Metabotropic glutamate receptor subtype 5 (mGluR5) is crucially implicated in the pathophysiology of Fragile X Syndrome (FXS); however, its dysfunction at the sub-cellular level, and related synaptic and cognitive phenotypes are unexplored. Here, we probed the consequences of mGluR5/Homer scaffold d...
Gespeichert in:
| Hauptverfasser: | , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
24 October 2017
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| In: |
Nature Communications
Year: 2017, Jahrgang: 8 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-017-01191-2 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1038/s41467-017-01191-2
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| Verfasserangaben: | Elisabetta Aloisi, Katy Le Corf, Julien Dupuis, Pei Zhang, Melanie Ginger, Virginie Labrousse, Michela Spatuzza, Matthias Georg Haberl, Lara Costa, Ryuichi Shigemoto, Anke Tappe-Theodor, Filippo Drago, Pier Vincenzo Piazza, Christophe Mulle, Laurent Groc, Lucia Ciranna, Maria Vincenza Catania & Andreas Frick |
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| 245 | 1 | 0 | |a Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice |c Elisabetta Aloisi, Katy Le Corf, Julien Dupuis, Pei Zhang, Melanie Ginger, Virginie Labrousse, Michela Spatuzza, Matthias Georg Haberl, Lara Costa, Ryuichi Shigemoto, Anke Tappe-Theodor, Filippo Drago, Pier Vincenzo Piazza, Christophe Mulle, Laurent Groc, Lucia Ciranna, Maria Vincenza Catania & Andreas Frick |
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| 520 | |a Metabotropic glutamate receptor subtype 5 (mGluR5) is crucially implicated in the pathophysiology of Fragile X Syndrome (FXS); however, its dysfunction at the sub-cellular level, and related synaptic and cognitive phenotypes are unexplored. Here, we probed the consequences of mGluR5/Homer scaffold disruption for mGluR5 cell-surface mobility, synaptic N-methyl-D-aspartate receptor (NMDAR) function, and behavioral phenotypes in the second-generation Fmr1 knockout (KO) mouse. Using single-molecule tracking, we found that mGluR5 was significantly more mobile at synapses in hippocampal Fmr1 KO neurons, causing an increased synaptic surface co-clustering of mGluR5 and NMDAR. This correlated with a reduced amplitude of synaptic NMDAR currents, a lack of their mGluR5-activated long-term depression, and NMDAR/hippocampus dependent cognitive deficits. These synaptic and behavioral phenomena were reversed by knocking down Homer1a in Fmr1 KO mice. Our study provides a mechanistic link between changes of mGluR5 dynamics and pathological phenotypes of FXS, unveiling novel targets for mGluR5-based therapeutics. | ||
| 650 | 4 | |a Animals | |
| 650 | 4 | |a Cognition | |
| 650 | 4 | |a Disease Models, Animal | |
| 650 | 4 | |a Female | |
| 650 | 4 | |a Fragile X Mental Retardation Protein | |
| 650 | 4 | |a Fragile X Syndrome | |
| 650 | 4 | |a Hippocampus | |
| 650 | 4 | |a Humans | |
| 650 | 4 | |a Male | |
| 650 | 4 | |a Mice | |
| 650 | 4 | |a Mice, Inbred C57BL | |
| 650 | 4 | |a Mice, Knockout | |
| 650 | 4 | |a Neuronal Plasticity | |
| 650 | 4 | |a Receptor, Metabotropic Glutamate 5 | |
| 650 | 4 | |a Receptors, N-Methyl-D-Aspartate | |
| 650 | 4 | |a Synapses | |
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