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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 modeling of postsynaptic plasticity to investigate how schizophrenia-associated genes regulate long-term potentiation (LTP) and depression (LTD). We combined our model with data from postmortem RNA 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 the anterior cingulate cortex, lead to impaired protein kinase A (PKA)-pathway-mediated LTP in synapses containing GluR1 receptors. We validated these findings using a genotyped electroencephalogram (EEG) dataset where polygenic risk scores for synaptic and ion channel-encoding genes as well as modulation of visual evoked potentials 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.<\/jats:p>","DOI":"10.1073\/pnas.2312511121","type":"journal-article","created":{"date-parts":[[2024,8,14]],"date-time":"2024-08-14T11:19:06Z","timestamp":1723634346000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":17,"title":["Genetic mechanisms for impaired synaptic plasticity in schizophrenia revealed by computational modeling"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7082-2507","authenticated-orcid":false,"given":"Tuomo","family":"M\u00e4ki-Marttunen","sequence":"first","affiliation":[{"name":"Biomedicine, Faculty of Medicine and Health Technology, Tampere University, Tampere 33720, Finland"},{"name":"Department of Biosciences, University of Oslo, Oslo 0371, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4711-2344","authenticated-orcid":false,"given":"Kim T.","family":"Blackwell","sequence":"additional","affiliation":[{"name":"Roy J. 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