Summary: Researchers have identified a system that impairs neural flexibility in people with schizophrenia, revealing the part of three essential proteins. Using mathematical modelling, the group explored how genomic alterations affect the body’s ability to strengthen or weaken neural connections, a vital process for memory and learning.
This discovery provides a fresh insight into how genetic variants associated with schizophrenia contribute to the symptoms and suggests possible targets for future treatments. The results may provide fresh information about schizophrenia’s development and new healing approaches.
Important Information:
- In dementia, three crucial proteins associated with neural plasticity are affected.
- Mathematical models can identify how biological variations impact brain connections.
- These proteins may be targeted for fresh dementia treatments in the study.
Origin: University of Tampere
A new study led by academics at Tampere University found a system that affects neural plasticity in those who are affected and has identified genes linked to dementia.
The researchers identified a possible role for three molecules in influencing the flexibility impairments in schizophrenia. The research does lead to the development of novel therapies.
Although there has been significant research into the link between biological variation and dementia, the genetic basis for this disorder is still a mystery. This is primarily because it has been impossible to examine how the various variants of each protein or how their altered expression affect the symptoms or phenotypes of dementia, which are the noticeable traits of the condition in specific patients, are affected.
Recent advances in mathematical neuroscience have made it possible for researchers to study medical disorders using computing simulations. Analysts at Tampere University collaborated with colleagues in Norway and the USA to create a mathematical model to examine the impact of molecular and genetic changes on neural flexibility in a new study.
For learning and memory, neuronal plasticity, a biological mechanism by which the strength of neural connections between neurons varies over time, is crucial. This method is thought to be a factor in schizophrenia’s development.
” Our mathematical model shows that certain alterations in the expression of genes associated with psychosis cause difficulties in neural plasticity,” according to our mathematical concept.
” This conclusion is supported by our successive analysis, where we adjusted genetic risk scores from genome-wide association studies to determine the unique contribution of plasticity-related genes to the risk of developing schizophrenia,” says Academy Research Fellow , Tuomo Mäki-Marttunen, the head author of the research paper.
Genome-wide association studies ( GWAS ) are used to identify statistical connections between various genome regions and a particular phenotype. These studies are particularly useful for investigating polygenic conditions, such as schizophrenia, which result from the interplay of hundreds or thousands of genetic variants.
The adjusted polygenic risk factors were found to have a correlated role with a deficient response to visual stimuli identified by our collaborators ‘ electroencephalograms ( EEGs ). This demonstrates that the presence of some genetic variants in plasticity-related genes can lead to a weak EEG response. Our computational model was therefore shown to accurately, or at least more reliably, predict a disruption of plasticity in schizophrenia,” Mäki-Marttunen says.
Next, it is necessary to take into account the effects of environmental factors.
The findings provide a mechanistic polygenic model for studying the single-cell level pathology associated with the condition, according to Mäki-Marttunen, making them a significant step forward in understanding the mechanisms underlying schizophrenia. Few computational models currently account for the contributions of multiple genes.
Animal studies have revealed how individual radical genetic mutations affect one another’s cellular and behavioral behaviors. In contrast, switching the whole genome between schizophrenia patients and healthy controls has led to new in vitro discoveries that have revealed how the phenotypes of schizophrenia are affected.
However, it’s challenging to figure out which genetic variants among the thousands are responsible for the observed changes and how the interplay of multiple genes affects the phenotypes of the condition is tested experimentally.
This gap is addressed by our computational modeling approach. We can examine the individual gene expression variations in terms of how schizophrenia manifests. In addition, we can easily investigate the combined effects of alterations in the expression of multiple genes, “explains Mäki-Marttunen.
The findings highlight three plasticity-related proteins that may significantly contribute to the schizophrenia-associated plasticity deficits. Mäki-Marttunen hopes that the findings will lead to more in-depth investigation into the role of these proteins in the condition. This could pave the way for new treatments.
Our study does not yet explain how the synaptic plasticity changes that are observed affect the symptoms of schizophrenia. To investigate the phenomena linked to schizophrenia symptoms, such as working memory, we need new computational models.
” In addition, our computational model should be expanded, so we could study the impact of not only hereditary but also environmental factors on the symptoms and phenotypes of schizophrenia”, Mäki-Marttunen says.
Funding: The study is a part of the Neural model building for psychiatric diseases – From genes to networks ( ModelPsych ) project, which runs from 2020 to 2025 and is funded by the Research Council of Finland.
Fact: What is gene expression?
- The step of gene expression is the transformation of the information encoded in a gene into a functional gene product, such as a protein or an RNA molecule.
- Gene expression involves two sequential steps: transcription, where the genetic information in DNA is transcribed into RNA, and translation, where that RNA molecule is used to synthesise a protein.
- Gene expression acts as an on/off switch that controls the number, type, and amount of proteins and RNA molecules produced.
- Misregulation of gene expression can lead to a wide range of illnesses because it is carefully controlled.
About this news item about schizophrenia and synaptic plasticity.
Author: Sari Laapotti
Source: University of Tampere
Contact: Sari Laapotti – University of Tampere
Image: The image is credited to Neuroscience News
Original Research: Closed access.
By Tuomo Mäki-Marttunen and colleagues,” Computational modeling revealed genetic explanations for schizophrenia’s impaired synaptic plasticity..” PNAS
Abstract
Computational modeling revealed genetic explanations for schizophrenia’s impaired synaptic plasticity.
The mechanisms behind these deficits are unknown, but schizophrenia phenotypes suggest that the disease’s cortical plasticity is impaired.
Numerous genes that control neuromodulation and plasticity have been implicated in genomic association studies, indicating that the plasticity deficits have a genetic origin.
We investigated how schizophrenia-associated genes regulate long-term potentiation ( LTP ) and depression ( LTD ) using biochemically detailed computational modeling of postsynaptic plasticity.
To examine the effects of altered expression of plasticity-regulating genes on the amplitude of LTP and LTD, we combined our model with data from postmortem RNA expression studies ( CommonMind gene-expression datasets ).
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 compared the polygenic risk scores for synaptic and ion channel-encoding genes, as well as the visual evoked potentials modulation, to 286 healthy controls, in an electroencephalographic ( EEG ) dataset that was used to validate these findings.
Our results provide a possible genetic mechanism for plasticity impairments in schizophrenia, which can lead to improved understanding and, ultimately, treatment of the disorder.
