Genetic mechanisms for impaired synaptic plasticity in schizophrenia revealed by computational modelling
Author:
Mäaki-Marttunen Tuomo, Blackwell Kim T., Akkouh Ibrahim, Shadrin Alexey, Valstad Mathias, Elvsåashagen Tobjørn, Linne Marja-Leena, Djurovic Srdjan, Einevoll Gaute T., Andreassen Ole A.ORCID
Abstract
AbstractSchizophrenia 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 observedpost 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.
Publisher
Cold Spring Harbor Laboratory
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