Transgenic Rodents and the Study of the Central Nervous System

The following view of transgenic studies applied to the understanding of brain function is written as a guide for neuroscientists who may be considering transgenesis techniques in the pursuit of their research. Although most important studies are covered, the chapter is not a comprehensive review of the literature. Rather, it is intended to convey the possibilities of a particular technique, and thus provide an indication of both strategies and attainable goals. In addition to providing information relevant to experimental design, particular areas of neuroscience that have benefited from transgenic approaches will also be discussed. Developmental neurobiology is not specifically addressed; for a recent review of genomic manipulations in neuron/ glial lineage analysis, see ref. 1 . The first section of the present chapter describes the use of transgenics to localize cis -acting elements within neuronal genes, which act in the mediation of cell-specific and regulated expression. Transgenic mice have been chosen, to an extent, by default as models for neuronal gene analysis since suitable, permanent neuronal cell lines are not available for transfection studies. Analysis of enhancer/promoter regions is a daunting undertaking in transgenics and there is a strong argument for combining these studies with DNA-mediated transfection experiments in heterologous cell lines. Transgenic animals are, however, much more than model expression systems; they provide a unique opportunity to study both the regulation and role of neuronal genes in the context of integrated brain systems. The second section deals with approaches to neuronal gene function, concerning both gain-of-function and loss-of-function techniques. In the third section, the use of transgenics in the molecular analysis of neurological syndromes is discussed: Are transgenic rodents useful models for human brain diseases? Finally, the capacity to generate neuronal cell lines following targeted expression of oncogenes to specific neurons is assessed. The transgenic studies discussed here employ mice as the experimental animal, and, with one exception, use DNA microinjection techniques (see Chapters 18 and 19 ) in the generation of transgenics. At the time of writing, no studies have been published in which neuronal transgenes are expressed in rats. However, the techniques for producing transgenic rats are now available (see Chapters 26 –31 ); given the ubiquitous use of rats by neuroscience investigators it is anticipated that the rat will be increasingly used to provide transgenic models for brain research.