{"doi":"10.1101/2021.10.01.462790","title":"INF2-mediated actin filament reorganization confers intrinsic resilience to neuronal ischemic injury","abstract":"ABSTRACT During early stages of ischemic brain injury, glutamate receptor hyperactivation mediates neuronal death via osmotic cell swelling. Here we show that ischemia and excess NMDA receptor activation – conditions that trigger neuronal swelling -- cause actin filaments to undergo a rapid and extensive reorganization within the somatodendritic compartment. Normally, F-actin is concentrated within dendritic spines, with relatively little F-actin in the dendrite shaft. However, beginning <5 min after incubation of neurons with NMDA, F-actin depolymerizes within dendritic spines and polymerizes into long, stable filament bundles within the dendrite shaft and soma. A similar “actinification” of the somatodendritic compartment occurs after oxygen/glucose deprivation in vitro , and in mouse brain after photothrombotic stroke in vivo . Following transient, sub-lethal NMDA exposure these actin changes spontaneously reverse within 1-2 hours. A combination of Na + , Cl - , water, and Ca 2+ entry are all necessary, but not individually sufficient, for induction of actinification. Spine F-actin depolymerization is also required. Actinification is driven by activation of the F-actin polymerization factor inverted formin-2 (INF2). Silencing of INF2 renders neurons more vulnerable to NMDA-induced membrane leakage and cell death, and formin inhibition markedly increases ischemic infarct severity in vivo . These results show that ischemia-induced actin filament reorganization within the dendritic compartment is an intrinsic pro-survival response that protects neurons from death induced by swelling.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":217900,"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":0.9481,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":815213,"name":"Steven L Jones","orcid":"0000-0002-6472-6754","position":1,"is_corresponding":false},{"id":815761,"name":"Yoko Yamaguchi-Shiraishi","orcid":null,"position":2,"is_corresponding":false},{"id":815762,"name":"Michael Lingelbach","orcid":null,"position":3,"is_corresponding":false},{"id":37858,"name":"Uri Manor","orcid":"0000-0002-9802-1955","position":4,"is_corresponding":false},{"id":276495,"name":"Tatyana Svitkina","orcid":null,"position":5,"is_corresponding":false},{"id":392271,"name":"Henry N. Higgs","orcid":"0000-0002-2917-9644","position":6,"is_corresponding":false},{"id":623396,"name":"Andy Y. Shih","orcid":"0000-0002-7839-392X","position":7,"is_corresponding":false},{"id":815214,"name":"Shelley Halpain","orcid":"0000-0002-7480-5157","position":8,"is_corresponding":false},{"id":815212,"name":"Barbara Calabrese","orcid":"0000-0003-2123-8221","position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":null,"created_at":"2026-07-18T23:53:24.683898Z","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":[]}