N-ethyl-N-nitrosourea mouse mutants in the dissection of behavioural and psychiatric disorders.

Twin and adoption studies have consistently implicated genetics in the aetiology of psychiatric and behavioural disorders. The identification of the genes and molecular pathways that are associated with these traits using linkage studies has been difficult because psychiatric disorders are almost always non-mendelian, heterogeneous, involve multiple genetic loci and are influenced significantly by environmental factors. Mouse models that are based on intermediate signatures of psychiatric disease and pharmacological responsiveness hold promise as a complementary approach to dissecting the molecular basis of neurobehavioural disorders. This has been made possible by the development and refinement of gene targeting technologies and the use of super-efficient chemical mutagens. N-ethyl-N-nitrosourea (ENU) mutagenesis in the mouse, when coupled to a battery of sensitive behavioural screens, is an effective way of creating and identifying novel mouse behavioural mutants. Here, the concept of screening for ENU mutants is introduced while progress with two behavioural screens, an "anxiety" screen and a circadian screen, are presented. It is hoped that the study of mouse mutants that have arisen from these screens will provide new insights into the genetic basis of abnormal behaviour and that they might lead to the development of novel therapeutic compounds for human psychiatric disease.