A Critical Review of Zebrafish Neurological Disease Models-2. Application: Functional and Neuroanatomical Phenotyping Strategies and Chemical Screens.

Extensive phylogenetic conservation of molecular pathways and neuroanatomical structures, associated with efficient methods for genetic modification, have been exploited increasingly to generate zebrafish models of human disease. A range of powerful approaches can be deployed to analyze these models with the ultimate goal of elucidating pathogenic mechanisms and accelerating efforts to find effective treatments. Unbiased neurobehavioral assays can provide readouts that parallel clinical abnormalities found in patients, although some of the most useful assays quantify responses that are not routinely evaluated clinically, and differences between zebrafish and human brains preclude expression of the full range of neurobehavioral abnormalities seen in disease. Imaging approaches that use fluorescent reporters and standardized brain atlases coupled with quantitative measurements of brain structure offer an unbiased means to link experimental manipulations to changes in neural architecture. Together, quantitative structural and functional analyses allow dissection of the cellular and physiological basis underlying neurological phenotypes. These approaches can be used as outputs in chemical modifier screens, which provide a major opportunity to exploit zebrafish models to identify small molecule modulators of pathophysiology that may be informative for understanding disease mechanisms and possible therapeutic approaches.