Gene Targeting and Transgenic Technologies

Recent progress in the development of molecular genetic methods enables the manipulation of genes in intact mammalian organisms. The power of such techniques to elucidate complex biological systems was initially recognized and exploited by developmental biologists and immunologists. More recently, the utility of these approaches for examining neural gene function in the context of the intact organism has led to their use in neuropsychopharmacology. Since the publication of the previous edition of this book, there has been an explosion in the application of molecular genetic technologies to study the regulation of complex behavior and its modulation by psychoactive drugs. For several decades, the ability to manipulate genes in organisms such as yeast, fruit flies, and nematodes has produced important insights into the regulation of a wide variety of complex biological processes. Limitations in the use of such organisms for research in neuropsychopharmacology arise from the marked organizational differences between the mammalian brain and the systems that govern behavior in these organisms. By contrast, a substantial degree of homology exists in the organization of the central nervous system (CNS) and in the complement of genes expressed across mammalian species. Currently, the mouse genome is by far the most accessible mammalian genome to manipulation. Procedures exist in the mouse for introducing new genes, expressing elevated levels of endogenous genes, and eliminating or altering the function of identified target genes. Mutant mouse models may be used for a number of purposes relevant to neuropsychopharmacologic research. For example, the impact of genetic mutations on the behavior of mutant mice may be examined, providing insights into the functional significance of particular gene products. In some cases, the manifestations (phenotypes) of these mu-