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Closing the translational gap between mutant mouse models and the clinical reality of psychotic illness
Colm M O'Tuathaigh1, John L Waddington2
1School of Medicine, Brookfield Health Sciences Complex, University College Cork, Cork, Ireland.
Abstract:
As animal models of psychotic illness become more refined, mutant mouse models have become increasingly prominent through their ability to inform on the structural, cellular and behavioural roles of genes associated with risk for psychosis via the phenotypic consequences of disruption of those genes. This review will consider recent advances in the field whereby mutant mouse models seek to reflect increasing knowledge of psychotic illness, focusing on four main themes. Firstly, recent GWAS and rare variant analyses have identified that disease-associated targets have not been previously implicated, thereby representing novel biological pathways in the illness, and this has implications for the modelling field. Secondly, the psychosis is disrespectful to conventional diagnostic boundaries, both clinically and in terms of pathobiology: it extends beyond schizophrenia to include several diagnostic categories and may be best captured in terms of psychopathological dimensions rather than/additional to such categories. Thirdly, a given risk gene (G) does not operate in isolation but, rather, appears to participate in complex interactions with environmental (E) risk factors, i.e., G×E interactions. Lastly, a given risk gene is likely to participate in complex, epistatic interactions with other risk genes, i.e., G×G interactions. Such studies constitute important steps in closing the translational gap between mutant mouse models and the clinical reality of psychotic illness.
Insights
Mutant mouse models are advancing our understanding of psychotic illness by revealing novel genetic pathways and complex gene-environment interactions. These models bridge the gap between basic research and clinical applications for psychosis.
Area of Science:
- Neuroscience
- Genetics
- Psychiatry
Background:
- Mutant mouse models are crucial for studying the genetic underpinnings of psychotic disorders.
- Advances in genetic analysis reveal novel risk genes and pathways implicated in psychosis.
- Psychotic illnesses transcend traditional diagnostic categories, suggesting underlying dimensional psychopathology.
Purpose of the Study:
- To review recent advancements in mutant mouse models for psychotic illness.
- To explore how these models reflect new knowledge on genetic risk, gene-environment interactions, and gene-gene interactions.
- To assess the translational relevance of these models for understanding psychosis.
Main Methods:
- Review of recent Genome-Wide Association Studies (GWAS) and rare variant analyses.
- Analysis of studies incorporating gene-environment (G×E) and gene-gene (G×G) interactions in mouse models.
- Focus on phenotypic consequences of gene disruption in mice to model psychosis.
Main Results:
- Identification of novel, previously un-implicated disease-associated targets.
- Recognition that psychosis involves complex interactions between genetic and environmental factors.
- Evidence for epistatic interactions among multiple risk genes (G×G).
Conclusions:
- Mutant mouse models are becoming more sophisticated in reflecting the complexity of psychotic illness.
- These models are vital for exploring novel biological pathways and the interplay of genetic and environmental risk factors.
- Continued development of these models is essential for closing the translational gap in psychosis research.
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