Genetic alterations of the murine serotonergic gene pathway: the neurodevelopmental basis of anxiety

The relative contribution of genetic and environmental factors in the configuration of behavioral differences is among the most prolonged and contentious controversies in intellectual history. Although current views emphasize the joint influence of genes and environmental sources during early brain development, the physiological complexities of multiple gene-gene and gene-environment interactions in the developmental neurobiology of fear and anxiety remain elusive. Variation in genes coding for proteins that control serotonin (5-hydroxytryptamine, 5-HT) system development and plasticity, establish 5-HT neuron identity, and modulate 5-HT receptor-mediated signal transduction as well as cellular pathways have been implicated in the genetics of anxiety and related disorders. This review selects anxiety and avoidance as paradigmatic traits and behaviors, and it focuses on mouse models that have been modified by deletion of genes coding for key players of serotonergic neurotransmission. In particular, pertinent approaches regarding phenotypic changes in mice bearing inactivation mutations of 5-HT receptors, 5-HT transporter, and monoamine oxidase A and other genes related to 5-HT signaling will be discussed and major findings highlighted.