{"doi":"10.1101/2023.09.07.556550","title":"TRPM2-CaMKII signaling drives excessive GABAergic synaptic inhibition following ischemia","abstract":"ABSTRACT Following an ischemic insult to the brain, there is an acute loss of GABAergic inhibitory synapses and an increase in excitatory/ inhibitory (E/I) imbalance that drives neuronal hyperexcitability. It is unknown whether this E/I imbalance persists at delayed timepoints and contributes to chronic impairments in memory and long-term potentiation (LTP) in the hippocampus following ischemic brain injury. Here, we reveal a shift to reduced E/I ratio in hippocampal CA1 neurons via a persistent increase in postsynaptic GABA A receptor mediated inhibitory responses and clustering days after a global ischemic insult. This enhancement of postsynaptic inhibitory function and clustering required activation of the Ca 2+ -permeable TRPM2 ion channel and the Ca 2+ -dependent kinase, CaMKII. Thus, we propose a mechanism in which acute downregulation of GABA A receptors is followed by a strengthening of inhibitory synapses at delayed periods after ischemia. Targeting this mechanism has therapeutic potential to recover hippocampal plasticity and cognitive function post-ischemia. GRAPHICAL ABSTRACT","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":411269,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9467,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":461062,"name":"Joshua D Garcia","orcid":"0000-0002-7572-2062","position":1,"is_corresponding":false},{"id":1192078,"name":"Heather O’Leary","orcid":null,"position":2,"is_corresponding":false},{"id":723278,"name":"Ami Haas","orcid":"0000-0001-9815-8954","position":3,"is_corresponding":false},{"id":406256,"name":"James E. Orfila","orcid":"0000-0003-1052-9795","position":4,"is_corresponding":false},{"id":688710,"name":"Erika Tiemeier","orcid":null,"position":5,"is_corresponding":false},{"id":345712,"name":"Nicholas Chalmers","orcid":"0009-0004-0778-6840","position":6,"is_corresponding":false},{"id":461063,"name":"Katharine R. Smith","orcid":"0000-0002-4762-7201","position":7,"is_corresponding":false},{"id":345716,"name":"Nidia Quillinan","orcid":"0000-0002-5708-8395","position":8,"is_corresponding":false},{"id":345717,"name":"Paco S. Herson","orcid":"0000-0002-3590-8751","position":9,"is_corresponding":false},{"id":624111,"name":"Amelia Burch","orcid":"0000-0001-8533-4293","position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:21:42.971455Z","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":[]}