CommentaryGenetic mouse models relevant to schizophrenia: Taking stock and looking forward
Section snippets
Which gene(s)?
There is no shortage of putative schizophrenia genes to study in a mouse model. Naturally, most work has focused on the genes which are considered to have the greatest depth and breadth of evidence for their involvement. Amongst these, Disrupted in schizophrenia 1 (DISC1) has been the most extensively studied, in a range of different mutants (Johnstone et al., 2011). Reflecting this focus, three papers in this issue pertain to DISC1 and are discussed later.
Other genetic mutants are studied not
What genetic manipulation?
The simplest and most widely used genetic manipulation is to knock the gene out. However, although this approach can be invaluable for identifying the role of a putative schizophrenia gene in brain function, the relevance to schizophrenia is limited in that there is no evidence for null mutations in the disorder. Heterozygous knockouts (e.g. Meck et al., 2012) in which ∼50% of expression is retained are better, particularly for genes where there is evidence for hemizygosity or a similar degree
Modeling gene–environment interactions
It is widely considered that genetic and environmental risk factors for schizophrenia do not act independently, but interactively (van Os et al., 2008). Hence, many investigators are studying the impact of an environmental intervention in genetic mouse models (Ayhan et al., 2009). The choice of intervention is, like the choice of gene, a decision affected by prior belief about the importance of the factor(s) in schizophrenia, as well as by practicalities, expertise, and interest. Environmental
Which phenotypes, which readouts?
Whichever genetic models and manipulations are used, a critical question remains as to which phenotype(s) to measure. These range increasingly broadly, from behavior to electrophysiology and morphology (with many specific readouts within each domain), and include modeling of symptoms and endophenotypes (e.g. Powell et al., 2009, Jaaro-Peled et al., 2010). Within electrophysiology, for example, Gandal et al. (2012) describe a recent addition to the phenotypic repertoire, the study of gamma
Conclusions
As the articles in this special issue illustrate, genetic mouse models relevant to schizophrenia are a thriving and productive research area. Equally, they demonstrate the complexities and decisions involved at each step, from choice of model, through experimental design and execution, to data interpretation. As the evidence for specific genes and genetic variants associated with schizophrenia becomes more compelling, and as the epidemiological and statistical evidence for gene–gene and
Acknowledgments
DP holds the University of Oxford Christopher Welch Scholarship. KS is funded by a studentship from the Wellcome Trust. JB is funded by a studentship from the Medical Research Council (MRC). WN holds a Department of Pharmacology studentship. KPL is a Wellcome Trust Career Development Fellow. DMB is a Wellcome Trust Senior Research Fellow. EMT is a Royal Society University Research Fellow. Our work is also supported by grants from MRC, BBSRC, and the BMA Margaret Temple Fellowship.
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Modeling Gene–Gene Interactions in Schizophrenia
2016, Handbook of Behavioral NeuroscienceCitation Excerpt :Double- and triple-knockout or transgenic models constitute one step toward addressing this challenge, but practical concerns restrict the viability of such approaches (Lyon, Kew, Corti, Harrison, & Burnet, 2008). Additionally, careful consideration must be taken when selecting which gene combinations to manipulate; promising candidates should include genes with a known biochemical pathway or genes within a candidate genomic locus (Arguello, Markx, Gogos, & Karayiorgou, 2010; Harrison et al., 2012). Modeling a disorder characterized by symptomatic and likely etiological heterogeneity is best addressed from a pragmatic standpoint by focusing on specific components of the disease phenotype rather than disease phenotype in its entirety (O’Tuathaigh, Desbonnet, & Waddington, 2014).
Closing the translational gap between mutant mouse models and the clinical reality of psychotic illness
2015, Neuroscience and Biobehavioral ReviewsCitation Excerpt :In contrast, some genes are up-regulated in schizophrenia or in association with disease risk alleles, and a more relevant manipulation is then transgenic over-expression. However, the magnitude of over-expression in a mouse can differ markedly from the clinical situation, complicating interpretation of phenotypic data (Harrison et al., 2012). Additionally, functional variants have not been identified for several genes associated with schizophrenia, precluding any attempt to generate a model with direct clinical relevance to the role of the gene in the disorder.
Translating advances in the molecular basis of schizophrenia into novel cognitive treatment strategies
2017, British Journal of PharmacologyGene-environment interactions in psychiatry: Nature, nurture, neuroscience
2016, Gene-Environment Interactions in Psychiatry: Nature, Nurture, Neuroscience