Random Mutagenesis Screen for Dominant Behavioral Mutations in Mice

Large-scale mutagenesis and screening for altered phenotypes have been used effectively in many (lower) model organisms to identify mutations in genes that control biological processes. In the mouse, the cost of maintaining the large breeding colonies necessary to screen for recessive mutations makes it important to consider alternate approaches such as region-specific saturation mutagenesis or screening for mutations with a dominant mode of inheritance. In this article, a pilot screen for (semi)dominant visible and behavioral mutations in the mouse induced by a potent chemical mutagen, N-ethyl-N-nitrosourea (ENU), is described. An efficient protocol for ENU mutagenesis and strain-specific differences in the effect of mutagen on the sterility period and long-term survival are reported. In addition to a description of the screen for abnormal circadian wheel running activity that was used previously, the suitability of a high-throughput screen of mutagenized progeny in the Porsolt swim test, used to test the efficacy of antidepressant agents, and in the prepulse inhibition of the acoustic startle response, used to detect anomalies in sensorimotor gating, is tested. By demonstrating strain specific differences and prescreening 100 G1 progeny of mutagenized males, the feasibility of using these behavioral assays for a large-scale screen is illustrated. In this review, details of a mutagenesis screen for behavioral abnormalities are described and issues important in the initial characterization of novel ENU-induced mutations are considered.