The genes and brains of mice and men

The elucidation of the human genome presents a challenge for psychiatry-determining the impact of thousands of genes on brain functions relevant to mental disorders. For both historical and practical reasons, the mouse has become the mammal of choice for applying molecular genetic approaches to gene function. A working draft of the mouse genome has led to estimates that a mouse version may be identified for 99% of human genes. In accord with their genomic homologies, humans and mice share numerous features of brain organization and behavioral responses to many pharmacological agents. Technologies enabling the precise experimental manipulation of the mouse genome provide unprecedented opportunities for exploring genetic contributions to the regulation of complex behavior and to the pathophysiology and treatment of psychiatric disease. The formidable array of mouse molecular genetic tools are applied for two general strategies: 1) exploring the function of particular genes by generating lines of mice with precise genetic alterations and 2) searching broadly for those genes that regulate a particular biological trait of interest. Essential to the effective use of these technologies is the implementation of sound strategies for discerning the impact of genetic manipulations on mouse behaviors relevant to psychiatric conditions. These approaches are having a major impact-examples relevant to psychiatric disorders are discussed. However, advances in implementing and interpreting behavioral assays have not kept pace with molecular genetic technologies. To maximize the extent to which the revolution in mammalian genetics may be effectively applied to psychiatric research, new technologies and strategies for mouse behavioral assessment must be developed.