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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 121; no. 34; p. e2312511121
• Main Authors: Mäki-Marttunen, Tuomo, Blackwell, Kim T., Akkouh, Ibrahim, Shadrin, Alexey, Valstad, Mathias, Elvsåshagen, Torbjørn, Linne, Marja-Leena, Djurovic, Srdjan, Einevoll, Gaute T., Andreassen, Ole A.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 20.08.2024; The National Academy of Sciences
• Subjects: Biological Sciences; Computational neuroscience; Computer Simulation; Cortex (cingulate); Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - metabolism; Datasets; EEG; Electroencephalography; Evoked Potentials, Visual - physiology; Gene expression; Genes; Glutamate receptors; Glutamic acid receptors (ionotropic); Humans; Ion channels; Kinases; Long-term potentiation; Long-Term Potentiation - genetics; Long-Term Synaptic Depression - genetics; Male; Mental disorders; Models, Neurological; Neuromodulation; Neuronal Plasticity - genetics; Neuroplasticity; Phenotypes; Phenotypic plasticity; Physical Sciences; Protein kinase A; Receptors, AMPA - genetics; Receptors, AMPA - metabolism; Schizophrenia; Schizophrenia - genetics; Schizophrenia - metabolism; Schizophrenia - physiopathology; Synapses; Synapses - genetics; Synapses - metabolism; Synaptic plasticity; Visual evoked potentials; Visual observation; Visual plasticity; postmortem RNA expression; GWAS; modeling of intracellular signaling pathways; schizophrenia; long-term potentiation (LTP)
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2312511121

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)-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.