Animals are effectively used to model prepulse inhibition, the ability of a detectable stimulus to inhibit or gate response to a secondary startling stimulus. Deficits in prepulse inhibition are seen in persons with schizophrenia, their relatives, and persons with schizotypal disorder. This application proposes to analyze the role of variation in two genes, Htr1a and Htr1b, and their products, the G-protein coupled serotonin receptors 5-HT1A and 5-HT1B, in sensorimotor gating processes in mice. Previous analyses of pharmacologic effects and knockout mice implicate these genes and receptors in regulating prepulse inhibiton, but it is unknown if or how they might play a role in determining differences between individuals or isogenic strains. Twenty genetically and phenotypically diverse inbred mouse strains will be surveyed for variation at three levels, (i) genetic sequence, (ii) brain receptor distribution, and (iii) agonist actions on prepulse inhibition. The hypothesis that genetic variation in Htr1a and Htr1b influences sensorimotor gating processes will be evaluated by direct association of strain haplotype and behavioral phenotype. Variation in the distribution of functional receptors in the brain will be tested as a neural phenotype mediating genetic and behavioral differences.
