--- _id: '746' abstract: - lang: eng text: 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. article_number: '1103' article_processing_charge: No author: - first_name: Elisabetta full_name: Aloisi, Elisabetta last_name: Aloisi - first_name: Katy full_name: Le Corf, Katy last_name: Le Corf - first_name: Julien full_name: Dupuis, Julien last_name: Dupuis - first_name: Pei full_name: Zhang, Pei last_name: Zhang - first_name: Melanie full_name: Ginger, Melanie last_name: Ginger - first_name: Virginie full_name: Labrousse, Virginie last_name: Labrousse - first_name: Michela full_name: Spatuzza, Michela last_name: Spatuzza - first_name: Matthias full_name: Georg Haberl, Matthias last_name: Georg Haberl - first_name: Lara full_name: Costa, Lara last_name: Costa - first_name: Ryuichi full_name: Shigemoto, Ryuichi id: 499F3ABC-F248-11E8-B48F-1D18A9856A87 last_name: Shigemoto orcid: 0000-0001-8761-9444 - first_name: Anke full_name: Tappe Theodor, Anke last_name: Tappe Theodor - first_name: Fillippo full_name: Drago, Fillippo last_name: Drago - first_name: Pier full_name: Vincenzo Piazza, Pier last_name: Vincenzo Piazza - first_name: Christophe full_name: Mulle, Christophe last_name: Mulle - first_name: Laurent full_name: Groc, Laurent last_name: Groc - first_name: Lucia full_name: Ciranna, Lucia last_name: Ciranna - first_name: Maria full_name: Catania, Maria last_name: Catania - first_name: Andreas full_name: Frick, Andreas last_name: Frick citation: ama: Aloisi E, Le Corf K, Dupuis J, et al. Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice. Nature Communications. 2017;8(1). doi:10.1038/s41467-017-01191-2 apa: Aloisi, E., Le Corf, K., Dupuis, J., Zhang, P., Ginger, M., Labrousse, V., … Frick, A. (2017). Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice. Nature Communications. Nature Publishing Group. https://doi.org/10.1038/s41467-017-01191-2 chicago: Aloisi, Elisabetta, Katy Le Corf, Julien Dupuis, Pei Zhang, Melanie Ginger, Virginie Labrousse, Michela Spatuzza, et al. “Altered Surface MGluR5 Dynamics Provoke Synaptic NMDAR Dysfunction and Cognitive Defects in Fmr1 Knockout Mice.” Nature Communications. Nature Publishing Group, 2017. https://doi.org/10.1038/s41467-017-01191-2. ieee: E. Aloisi et al., “Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice,” Nature Communications, vol. 8, no. 1. Nature Publishing Group, 2017. ista: Aloisi E, Le Corf K, Dupuis J, Zhang P, Ginger M, Labrousse V, Spatuzza M, Georg Haberl M, Costa L, Shigemoto R, Tappe Theodor A, Drago F, Vincenzo Piazza P, Mulle C, Groc L, Ciranna L, Catania M, Frick A. 2017. Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice. Nature Communications. 8(1), 1103. mla: Aloisi, Elisabetta, et al. “Altered Surface MGluR5 Dynamics Provoke Synaptic NMDAR Dysfunction and Cognitive Defects in Fmr1 Knockout Mice.” Nature Communications, vol. 8, no. 1, 1103, Nature Publishing Group, 2017, doi:10.1038/s41467-017-01191-2. short: E. Aloisi, K. Le Corf, J. Dupuis, P. Zhang, M. Ginger, V. Labrousse, M. Spatuzza, M. Georg Haberl, L. Costa, R. Shigemoto, A. Tappe Theodor, F. Drago, P. Vincenzo Piazza, C. Mulle, L. Groc, L. Ciranna, M. Catania, A. Frick, Nature Communications 8 (2017). date_created: 2018-12-11T11:48:17Z date_published: 2017-12-01T00:00:00Z date_updated: 2023-09-27T12:27:30Z day: '01' ddc: - '571' department: - _id: RySh doi: 10.1038/s41467-017-01191-2 external_id: isi: - '000413571300004' file: - access_level: open_access checksum: 99ceee57549dc0461e3adfc037ec70a9 content_type: application/pdf creator: system date_created: 2018-12-12T10:17:32Z date_updated: 2020-07-14T12:47:58Z file_id: '5287' file_name: IST-2017-915-v1+1_s41467-017-01191-2.pdf file_size: 1841650 relation: main_file file_date_updated: 2020-07-14T12:47:58Z has_accepted_license: '1' intvolume: ' 8' isi: 1 issue: '1' language: - iso: eng month: '12' oa: 1 oa_version: Published Version publication: Nature Communications publication_identifier: issn: - '20411723' publication_status: published publisher: Nature Publishing Group publist_id: '6921' pubrep_id: '915' quality_controlled: '1' scopus_import: '1' status: public title: Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice tmp: image: /images/cc_by.png legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0) short: CC BY (4.0) type: journal_article user_id: c635000d-4b10-11ee-a964-aac5a93f6ac1 volume: 8 year: '2017' ...