The Use of Transgenes and Mutations in the Mouse to Study the Genetic Basis of Locomotor Hyperactivity

As the mouse genome becomes more accessible to experimental manipulation, it is becoming feasible to assess how genes influence the expression of specific behavioral traits. The mouse mutant coloboma exhibits extreme hyperactivity resulting from an approximately 2-cM deletion on mouse Chromosome 2. This deletion includes the gene encoding SNAP-25, a neuron-specific protein implicated in exocytotic neurotransmitter release. Because a deficit in this gene product might contribute to the expression of hyperactivity, a transgene expressing SNAP-25 was bred into the coloboma mouse genome to replace the missing SNAP-25 and rescue the hyperactivity. The Snap transgene was indeed sufficient to ameliorate the locomotor excesses exhibited by these mice, suggesting that SNAP-25 plays a central role in the expression of hyperactivity. In the course of designing and executing this experiment, several methodologic issues pertinent to manipulating the mouse genome in the context of a behavioral question were presented. These issues are discussed in light of the unique properties of the mouse as a behavioral genetic tool.