Genetic mechanisms for impaired synaptic plasticity in schizophrenia revealed by computational modeling

• 成果类型: Article
• 署名作者: Maki-Marttunen, Tuomo; Blackwell, Kim T.; Akkouh, Ibrahim; Shadrin, Alexey; Valstad, Mathias; Elvsashagen, Torbjorn; Linne, Marja-Leena; Djurovic, Srdjan; Einevoll, Gaute T.; Andreassen, Ole A.
• 署名单位: Tampere University; University of Oslo; University of Iowa; University of Oslo; University of Oslo; University of Oslo; University of Oslo; Norwegian Institute of Public Health (NIPH); University of Oslo; Norwegian University of Life Sciences; University of Oslo; University of Oslo
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8830
• DOI: 10.1073/pnas.2312511121
• 发表日期: 2024-08-20
• 关键词: long-term potentiation; visual cortical plasticity; neurogranin phosphorylation; dependent plasticity; neurotrophic factor; prefrontal cortex; RISK; brain; ampa; expression

摘要

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 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)-pathwaymediated 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.