Using Zebrafish to Unravel the Genetics of Complex Brain Disorders

The zebrafish has been prominently utilized in developmental biology for the past three decades and numerous genetic tools have been developed for it. Due to the accumulated genetic knowledge the zebrafish has now been considered an excellent research tool in other disciplines of biology too, including behavioral neuroscience and behavior genetics. Given the complexity of the vertebrate brain in general and the large number of human brain disorders whose mechanisms remain mainly unmapped in particular, there is a substantial need for appropriate laboratory research organisms that may be utilized to model such diseases and facilitate the analysis of their mechanisms. The zebrafish may have a bright future in this research field. It offers a compromise between system complexity (it is a vertebrate similar in many ways to our own species) and practical simplicity (it is small, easy to keep, and it is prolific). These features have made zebrafish an excellent choice, for example, for large scale mutation and drug screening. Such approaches may have a chance to tackle the potentially large number of molecular targets and mechanisms involved in complex brain disorders. However, although promising, the zebrafish is admittedly a novel research tool and only few empirical examples exist to support this claim. In this chapter, first I briefly review some of the rapidly evolving genetic methods available for zebrafish. Second, I discuss some promising examples for how zebrafish have been used to model and analyze molecular mechanisms of complex brain disorders. Last, I present some recently developed zebrafish behavioral paradigms that may have relevance for a spectrum of complex human brain disorders including those associated with abnormalities of learning and memory, fear and anxiety, and social behavior. Although at this point co-application of the genetics and behavioral approaches is rare with zebrafish, I argue that the rapid accumulation of knowledge in both of these disciplines will make zebrafish a prominent research tool for the genetic analysis of complex brain disorders.