{"doi":"10.1016/j.celrep.2025.115311","title":"Non-ionotropic signaling through the NMDA receptor GluN2B carboxy-terminal domain drives dendritic spine plasticity and reverses fragile X phenotypes","abstract":"N-methyl-D-aspartate (NMDA)-induced spine shrinkage proceeds independently of ion flux and requires the initiation of de novo protein synthesis. Using subtype-selective pharmacological and genetic tools, we find that structural plasticity is dependent on ligand binding to GluN2B-containing NMDA receptors (NMDARs) and signaling via the GluN2B carboxy-terminal domain (CTD). Disruption of non-ionotropic signaling by replacing the GluN2B CTD with the GluN2A CTD leads to an increase in spine density, dysregulated basal protein synthesis, exaggerated long-term depression mediated by G-protein-coupled metabotropic glutamate receptors (mGluR-LTD), and epileptiform activity reminiscent of phenotypes observed in the Fmr1 knockout (KO) model of fragile X syndrome. By crossing the Fmr1 KO mice with animals in which the GluN2A CTD has been replaced with the GluN2B CTD, we observe a correction of these core fragile X phenotypes. These findings suggest that non-ionotropic NMDAR signaling through GluN2B may represent a novel therapeutic target for the treatment of fragile X and related causes of intellectual disability and autism.","journal":"Cell Reports","year":2025,"id":512790,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.949,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1049833,"name":"Aurore Thomazeau","orcid":"0000-0002-7668-2867","position":1,"is_corresponding":false},{"id":811114,"name":"Peter S.B. Finnie","orcid":"0000-0003-2806-9600","position":2,"is_corresponding":false},{"id":1359114,"name":"Maxwell J. Heinrich","orcid":"0009-0004-2368-3470","position":3,"is_corresponding":false},{"id":344833,"name":"Arnold J. Heynen","orcid":"0000-0003-4313-7405","position":4,"is_corresponding":false},{"id":87274,"name":"Noboru H. Komiyama","orcid":"0000-0001-9960-3597","position":5,"is_corresponding":false},{"id":87276,"name":"Seth G. N. Grant","orcid":"0000-0001-8732-8735","position":6,"is_corresponding":false},{"id":394992,"name":"Frank S. Menniti","orcid":"0000-0003-2612-9534","position":7,"is_corresponding":false},{"id":1236882,"name":"Emily K. Osterweil","orcid":"0000-0003-0582-2284","position":8,"is_corresponding":false},{"id":261781,"name":"Mark F. Bear","orcid":"0000-0002-9903-2541","position":9,"is_corresponding":false},{"id":303912,"name":"Stephanie A. Barnes","orcid":"0000-0002-8764-5666","position":0,"is_corresponding":true}],"reference_count":95,"raw_metadata":null,"created_at":"2026-07-19T02:48:11.233009Z","pmid":"39983718","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}