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

Tuomo Mäaki-Marttunen; Kim T. Blackwell; Ibrahim Akkouh; Alexey Shadrin; Mathias Valstad; Tobjørn Elvsåashagen; Marja-Leena Linne; Srdjan Djurovic; Gaute T. Einevoll; Ole A. Andreassen

doi:10.1101/2023.06.14.544920

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

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Open access

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

Tuomo Mäaki-Marttunen, Kim T. Blackwell, Ibrahim Akkouh, Alexey Shadrin, Mathias Valstad, Tobjørn Elvsåashagen, Marja-Leena Linne, Srdjan Djurovic, Gaute T. Einevoll and Ole A. Andreassen

bioRxiv

Cold Spring Harbor Laboratory

06/14/2023

DOI: 10.1101/2023.06.14.544920

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Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

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.

Details

Title: Subtitle: Genetic mechanisms for impaired synaptic plasticity in schizophrenia revealed by computational modelling
Creators: Tuomo Mäaki-Marttunen
Kim T. Blackwell - George Mason University
Ibrahim Akkouh - Oslo University Hospital
Alexey Shadrin - Oslo University Hospital
Mathias Valstad - Norwegian Institute of Public Health
Tobjørn Elvsåashagen
Marja-Leena Linne - Tampere University
Srdjan Djurovic - Oslo University Hospital
Gaute T. Einevoll - Norwegian University of Life Sciences
Ole A. Andreassen - University of Oslo
Resource Type: Preprint
Publication Details: bioRxiv
DOI: 10.1101/2023.06.14.544920
Publisher: Cold Spring Harbor Laboratory
Language: English
Date posted: 06/14/2023
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Iowa Neuroscience Institute
Record Identifier: 9984573819102771

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