Abstract
Exploration of the effects of schizophrenia-associated genes on cortical plasticity: a computational modelling study
Neuroscience 2022 (San Diego, California, USA, 11/12/2022–11/16/2022)
11/14/2022
Abstract
Symptoms and electrophysiological phenotypes of schizophrenia implicate altered synaptic plasticity as a potential cellular-level disease mechanism. Supporting this hypothesis, genes encoding intracellular signaling and membrane proteins associated with plasticity, including ion channels and neurotransmitter receptors, have been consistently identified as risk genes in the recent genome-wide association studies (GWAS). Here, we applied a recent biochemically detailed model of cortical synaptic plasticity (Mäki-Marttunen et al. Elife 9 (2020): e55714) to explore this hypothesis. This mass action based, computational model describes the signaling networks connecting neuromodulatory receptors with phosphorylation of AMPA receptors and the consequent insertion to or removal from the spine membrane. We concentrated on the genes identified in the most recent GWAS of schizophrenia (Trubetskoy et al. Nature 604.7906 (2022): 502-508). We analysed the effects of alterations in the model parameters corresponding the functions of proteins encoded by these genes. We found that while long-term potentiation and depression (including spike-timing dependent plasticity) in the neocortex remained unaltered by some of these genes, they were significantly altered by others. Mild alterations (±20%) of expression levels of the schizophrenia-associated genes could lead to strengthened or weakened plasticity, and importantly, specific combinations of these variants led to crucial impairments of induction and maintenance of long-term plasticity. We discuss the implications of these predictions on electrophysiological phenotypes of schizophrenia, and in particular, mismatch negativity and plasticity of visual evoked potentials. Our results suggest polygenic mechanisms behind altered synaptic plasticity in schizophrenia that may underlie the often complex endophenotypes and symptoms.
Details
- Title: Subtitle
- Exploration of the effects of schizophrenia-associated genes on cortical plasticity: a computational modelling study
- Creators
- Tuomo Mäki-Marttunen - Simula Research LaboratoryKim T Blackwell (Author) - University of Iowa, Roy J. Carver Department of Biomedical EngineeringJ VerhellenG T EinevollM-L LinneSrdjan Djurovic - Oslo University HospitalT ElvsåshagenO A Andreassen (Author) - University of Oslo
- Resource Type
- Abstract
- Event
- Neuroscience 2022 (San Diego, California, USA, 11/12/2022–11/16/2022)
- Comment
- Poster. UNINETT Sigma2 resources (project NN9529K) and CSC (project 2003397) were used for simulations
- Language
- English
- Date published
- 11/14/2022
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Iowa Neuroscience Institute
- Record Identifier
- 9984585852402771
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