{"doi":"10.1073/pnas.2502997122","title":"Nonionic signaling rapidly remodels postsynaptic DLG to induce retrograde homeostatic plasticity","abstract":"<jats:p>\n                    Synapses must be resilient to the challenges they confront during development, experience, disease, and aging. A conserved form of adaptive plasticity, observed at the glutamatergic\n                    <jats:italic toggle=\"yes\">Drosophila</jats:italic>\n                    neuromuscular junction (NMJ), is expressed following acute pharmacological blockade of postsynaptic glutamate receptors (GluRs). This challenge is counteracted by enhanced presynaptic neurotransmitter release to maintain stable synaptic strength. This retrograde form of homeostatic plasticity is termed presynaptic homeostatic potentiation (PHP). How retrograde PHP signaling is acutely induced in the postsynaptic compartment is unknown. Here, we demonstrate that acute PHP induction does not require reductions in ionic flow through GluRs. Rather, pharmacological blockade provokes nanoscale changes in GluR organization that propagates remodeling of the postsynaptic apparatus. These postsynaptic structural changes are necessary for the presynaptic remodeling that characterizes PHP, including enhanced active zone intensity. Next, using a CRISPR-based genetic screen, we identify Discs large (DLG), the fly homolog of mammalian PSD-95, as a key postsynaptic substrate selectively required for acute PHP signaling. Finally, we find that homeostatic remodeling of both pre- and postsynaptic compartments persists in the absence of synaptic activity. Together, we propose that acute pharmacological perturbation of GluRs triggers activity-independent conformational signaling that is propagated throughout the postsynaptic apparatus, transmitting retrograde information that rapidly induces PHP.\n                  </jats:p>","journal":"Proceedings of the National Academy of Sciences","year":2025,"id":612990,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"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":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1131197,"name":"Sarah Perry","orcid":null,"position":1,"is_corresponding":false},{"id":725494,"name":"Christine Chen","orcid":"0000-0002-8222-1469","position":2,"is_corresponding":false},{"id":1187833,"name":"Jiawen Chen","orcid":"0000-0002-6307-0335","position":3,"is_corresponding":false},{"id":1578821,"name":"Jin Zhuang","orcid":null,"position":4,"is_corresponding":false},{"id":382966,"name":"Yifu Han","orcid":"0000-0002-1201-654X","position":5,"is_corresponding":false},{"id":382965,"name":"Pragya Goel","orcid":"0000-0002-6348-4909","position":6,"is_corresponding":false},{"id":382968,"name":"Dion Dickman","orcid":"0000-0003-1884-284X","position":7,"is_corresponding":false},{"id":906943,"name":"Chengjie Qiu","orcid":"0000-0002-5382-8325","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Nonionic signaling rapidly remodels postsynaptic DLG to induce retrograde homeostatic plasticity","abstract":"<jats:p>\n                    Synapses must be resilient to the challenges they confront during development, experience, disease, and aging. A conserved form of adaptive plasticity, observed at the glutamatergic\n                    <jats:italic toggle=\"yes\">Drosophila</jats:italic>\n                    neuromuscular junction (NMJ), is expressed following acute pharmacological blockade of postsynaptic glutamate receptors (GluRs). This challenge is counteracted by enhanced presynaptic neurotransmitter release to maintain stable synaptic strength. This retrograde form of homeostatic plasticity is termed presynaptic homeostatic potentiation (PHP). How retrograde PHP signaling is acutely induced in the postsynaptic compartment is unknown. Here, we demonstrate that acute PHP induction does not require reductions in ionic flow through GluRs. Rather, pharmacological blockade provokes nanoscale changes in GluR organization that propagates remodeling of the postsynaptic apparatus. These postsynaptic structural changes are necessary for the presynaptic remodeling that characterizes PHP, including enhanced active zone intensity. Next, using a CRISPR-based genetic screen, we identify Discs large (DLG), the fly homolog of mammalian PSD-95, as a key postsynaptic substrate selectively required for acute PHP signaling. Finally, we find that homeostatic remodeling of both pre- and postsynaptic compartments persists in the absence of synaptic activity. Together, we propose that acute pharmacological perturbation of GluRs triggers activity-independent conformational signaling that is propagated throughout the postsynaptic apparatus, transmitting retrograde information that rapidly induces PHP.\n                  </jats:p>","is_dataset_classified":null,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"41296724","pmcid":"PMC12684909","openalex_id":"https://openalex.org/W4416714802","authors":[],"funders":[{"funder_name":"HHS | NIH | National Institute of Neurological Disorders and Stroke","grant_id":"NS091548","title":null},{"funder_name":"NINDS NIH HHS","grant_id":"R01 NS091546","title":null}],"total_grants":2,"fwci":1.1228,"citation_percentile":0.79766134,"influential_citations":0,"citation_trend":[{"year":2026,"count":2}],"oa_status":"hybrid","license":"cc-by-nc-nd","oa_locations":[{"url":"https://doi.org/10.1073/pnas.2502997122","host_type":"journal"},{"url":"https://doi.org/10.1073/pnas.2502997122","host_type":"publisher"},{"url":"https://pnas.org/doi/pdf/10.1073/pnas.2502997122","host_type":"publisher"},{"url":"https://pubmed.ncbi.nlm.nih.gov/41296724","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12684909/","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC12684909","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC12684909?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Neurobiology and Insect Physiology Research","Neuroscience and Neuropharmacology Research","Ion channel regulation and function","Animals","Drosophila Proteins","Neuronal Plasticity","Neuromuscular Junction","Homeostasis","Signal Transduction","Receptors, Glutamate","Drosophila melanogaster","Synapses","Synaptic Transmission","Drosophila","Tumor Suppressor Proteins"],"mesh_terms":["Animals","Drosophila","Drosophila melanogaster","Homeostasis","Synaptic Transmission","Neuromuscular Junction","Neuronal Plasticity","Synapses","Signal Transduction","Receptors, Glutamate","Tumor Suppressor Proteins","Drosophila Proteins"],"keywords":["Postsynaptic potential","Retrograde signaling","Homeostatic plasticity","Excitatory postsynaptic potential","Post-tetanic potentiation","Nonsynaptic plasticity","Postsynaptic density","Neurotransmitter receptor","Long-term potentiation","Drosophila","Synapse","Glutamate receptor","Neuromuscular junction"],"sdg_mappings":[],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-02T05:59:56.424587Z","pmid":null,"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":[]}