{"doi":"10.3389/fphar.2025.1568908","title":"Loss of SynDIG4/PRRT1 alters distribution of AMPA receptors in Rab4- and Rab11-positive endosomes and impairs basal AMPA receptor recycling","abstract":"The transmembrane protein Synapse Differentiation Induced Gene 4 (SynDIG4) functions as an auxiliary factor of AMPA receptors (AMPARs) and plays a critical role in excitatory synaptic plasticity as well as hippocampal-dependent learning and memory. Mice lacking SynDIG4 have reduced surface expression of GluA1 and GluA2 and are impaired in single tetanus-induced long-term potentiation and NMDA receptor (NMDAR)-dependent long-term depression. These findings suggest that SynDIG4 may play an important role in regulating AMPAR distribution through intracellular trafficking mechanisms; however, the precise roles by which SynDIG4 governs AMPAR distribution remain unclear. Here, we characterized the endocytosis and recycling of GluA1-containing AMPARs under basal conditions. We did not observe any change in baseline endocytosis; however, we did observe a significant decrease in recycling of GluA1-containing AMPARs in cultured hippocampal neurons from mice lacking SynDIG4. This resulted in a significant increase in the levels of internal GluA1 and GluA2, along with greater colocalization of these subunits with Rab4-positive recycling endosomes. Notably, the overlap between Rab4-positive and Rab11-positive vesicles was elevated in hippocampal neurons lacking SynDIG4, suggesting an impairment in the trafficking between these compartments. Furthermore, our findings revealed a reduction in surface GluA1 within synaptic regions of hippocampal neurons lacking SynDIG4. Collectively, these results indicate that SynDIG4 regulates the distribution of GluA1-containing AMPARs via the Rab4-dependent endosomal recycling pathway, thereby maintaining AMPAR levels at synaptic regions under baseline conditions. This regulatory function of SynDIG4 may contribute to the deficits in GluA1-dependent synaptic plasticity and impairment of hippocampal-dependent behaviors observed in SynDIG4 deficient mice.","journal":"Frontiers in Pharmacology","year":2025,"id":532399,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9537,"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":513018,"name":"Elva Dı́az","orcid":"0000-0002-3287-7515","position":1,"is_corresponding":false},{"id":957825,"name":"Chun-Wei He","orcid":"0000-0002-9852-8852","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T02:51:23.237536Z","pmid":"40469985","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":[]}