{"doi":"10.1016/j.celrep.2025.115302","title":"Loss of the proton-activated chloride channel in neurons impairs AMPA receptor endocytosis and LTD via endosomal hyper-acidification","abstract":"Hippocampal long-term potentiation (LTP) and long-term depression (LTD) are forms of synaptic plasticity, thought to be the molecular basis of learning and memory, dependent on dynamic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) trafficking. Alteration of endosomal pH negatively affects synaptic transmission and neural development, but it is unclear how pH is involved in AMPAR trafficking. We show that the proton-activated chloride (PAC) channel localizes to early and recycling endosomes in neurons and prevents endosome hyper-acidification. Loss of PAC reduces AMPAR endocytosis during chemical LTD in primary neurons, while basal trafficking and LTP are unaffected. Pyramidal neuron-specific PAC knockout mice have impaired hippocampal LTD, but not LTP, and perform poorly in the Morris water maze reversal test, exhibiting impaired behavioral adaptation. We conclude that proper maintenance of endosomal pH by PAC in neurons is important during LTD to regulate AMPAR trafficking in a manner critical for animal physiology and behavior.","journal":"Cell Reports","year":2025,"id":517043,"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":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9511,"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":332215,"name":"Junhua Yang","orcid":"0000-0003-4117-7569","position":1,"is_corresponding":false},{"id":320468,"name":"Bian Liu","orcid":"0000-0001-9166-693X","position":2,"is_corresponding":false},{"id":1354222,"name":"Chaohua Jiang","orcid":"0000-0001-5675-8441","position":3,"is_corresponding":false},{"id":941216,"name":"Nicholas Koylass","orcid":"0000-0003-3078-1867","position":4,"is_corresponding":false},{"id":1354223,"name":"Zhe Zhang","orcid":"0000-0002-6892-2525","position":5,"is_corresponding":false},{"id":636616,"name":"Shuying Sun","orcid":"0000-0002-8449-7370","position":6,"is_corresponding":false},{"id":275418,"name":"Richard L. Huganir","orcid":"0000-0001-9783-5183","position":7,"is_corresponding":false},{"id":302485,"name":"Zhaozhu Qiu","orcid":"0000-0002-9122-6077","position":8,"is_corresponding":false},{"id":884412,"name":"Kevin Hong Chen","orcid":"0000-0002-5421-1538","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-19T02:48:54.768083Z","pmid":"39946237","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":[]}