Mouse Models of the 5-HTTLPR × Stress Risk Factor for Depression

Abstract

The incidence of mood disorders is known to be influenced by both genetic as well as environmental factors. Increasingly, however it is becoming clear that few genetic and environmental factors act alone, but that instead they regularly act in concert to determine predisposition to psychiatric disorders. Quite a few cases now have been reported in which stratification of subjects by exposure to environmental pathogens has been shown to alter the association between specific genetic variants and mental illness. The best studied of such measured gene-by-environment risk factors for mental illness is the increased risk for major depression reported among persons carrying the short variant (S allele) of a functional polymorphism in the serotonin transporter (5-HTT, SLC6A4) gene promoter and who have been exposed to stressful life events. Recently, a large number of laboratories have tried to model the interaction between 5-HTTLPR genotype and early/adult stress in mouse. Findings from their studies have helped to define the rodent orthologs of the environmental stressors and behavioral traits involved in risk for depression. Furthermore, several of these studies attempted to identify changes in molecular substrates that might underlie the 5-HTT x stress risk factor, pointing to the hippocampus and frontal cortex as critical brain structures involved in the interaction between 5-HTT gene variation and early and adult stress, respectively. These results will serve to help inform clinical research into the origins of major depression and other mental illnesses with interacting genetic and environmental risk factors.