{"doi":"10.1101/2023.06.14.544920","title":"Genetic mechanisms for impaired synaptic plasticity in schizophrenia revealed by computational modelling","abstract":"Abstract Schizophrenia phenotypes are suggestive of impaired cortical plasticity in the disease, but the mechanisms of these deficits are unknown. Genomic association studies have implicated a large number of genes that regulate neuromodulation and plasticity, indicating that the plasticity deficits have a genetic origin. Here, we used biochemically detailed computational modelling of post-synaptic plasticity to investigate how schizophrenia-associated genes regulate long-term potentiation (LTP) and depression (LTD). We combined our model with data from post-mortem mRNA expression studies (CommonMind gene-expression datasets) to assess the consequences of altered expression of plasticity-regulating genes for the amplitude of LTP and LTD. Our results show that the expression alterations observed post mortem , especially those in anterior cingulate cortex, lead to impaired PKA-pathway-mediated LTP in synapses containing GluR1 receptors. We validated these findings using a genotyped EEG dataset where polygenic risk scores for synaptic and ion channel-encoding genes as well as modulation of visual evoked potentials (VEP) were determined for 286 healthy controls. Our results provide a possible genetic mechanism for plasticity impairments in schizophrenia, which can lead to improved understanding and, ultimately, treatment of the disorder.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":408551,"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":0.9403,"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":352648,"name":"Kim T. Blackwell","orcid":"0000-0003-4711-2344","position":1,"is_corresponding":false},{"id":319850,"name":"Ibrahim A. Akkouh","orcid":"0000-0002-6810-9999","position":2,"is_corresponding":false},{"id":34326,"name":"Alexey Shadrin","orcid":"0000-0002-7467-250X","position":3,"is_corresponding":false},{"id":1187774,"name":"Mathias Valstad","orcid":"0000-0002-1728-7541","position":4,"is_corresponding":false},{"id":1188196,"name":"Tobjørn Elvsåashagen","orcid":null,"position":5,"is_corresponding":false},{"id":1187775,"name":"Marja‐Leena Linne","orcid":"0000-0003-2577-7329","position":6,"is_corresponding":false},{"id":279140,"name":"Srdjan Djurovic","orcid":"0000-0002-8140-8061","position":7,"is_corresponding":false},{"id":587315,"name":"Gaute T. Einevoll","orcid":"0000-0002-5425-5012","position":8,"is_corresponding":false},{"id":52934,"name":"Ole A. Andreassen","orcid":"0000-0002-4461-3568","position":9,"is_corresponding":false},{"id":1188195,"name":"Tuomo Mäaki-Marttunen","orcid":null,"position":0,"is_corresponding":true}],"reference_count":123,"raw_metadata":null,"created_at":"2026-07-19T01:21:18.414003Z","pmid":"37398070","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":[]}