Mice mutant for genes associated with schizophrenia: Common phenotype or distinct endophenotypes?

Lieve Desbonnet, John L. Waddington, Colm M.P. O’Tuathaigh

Schizophrenia is a complex neuropsychiatric disorder whose etiology involves a mixture of genetic and environmental factors. By virtue of this complexity, schizophrenia is a field of research in which a number of key technologies converge: in particular, identification of putative susceptibility genes through association studies in clinical populations leads to investigation of the behavioural roles of these genes by targeted manipulation in mice and their phenotypic characterisation ('gene-driven' approach); in a complementary manner, identification of putative pathophysiological processes and therapeutic pathways leads to investigation of behavioural phenotype in mice mutant for genes regulating such processes and pathways ('phenotype-driven' approach). As several susceptibility genes for schizophrenia and numerous genes implicated in the pathophysiology of schizophrenia have now been genetically manipulated in mice, it is timely to consider the roles of these genes in abnormal brain development and the ontogeny of putative schizophrenia-like phenotypes. The aim of this review is to outline existing knowledge from mutant studies concerning the contribution of these genes to the development of a common schizophrenia phenotype vis-à-vis discrete schizophrenia endophenotypes. Emphasis is also placed on the importance of studying gene x environment and gene x gene interactions, as well as addressing methodological issues related to genetic modelling and phenotyping strategies.