Targeting the murine serotonin transporter: insights into human neurobiology

Key Points Serotonin's suspected involvement in emotions such as anxiety and depression in behavioural and neuropsychiatric disorders, as well as in many physiological processes, has been suggested by indirect evidence over many decades. More recently, specific evidence of a major role for serotonin in human disorders was obtained from evaluations of gene variants, such as the 5-HTTLPR in the gene that encodes the serotonin transporter (SERT), in human lymphoblasts, as well as from studies of post-mortem brain tissue and dynamic brain imaging of SERT. Even stronger evidence of the roles of serotonin and SERT has emerged over the past decade from the use of genetic engineering technologies to produce partially and completely SERT-deficient mice and mice that overexpress SERT. Anxiety-like behaviours and other behaviours, as well as over 50 different changes in brain serotonin homeostasis, have been documented in these mice. These were accompanied by differential responses to anti-anxiety and antidepressant drugs, as well as brain anatomical and physiological changes. Some of these changes are different from those that are produced by selective serotonin reuptake inhibitors (SSRIs; drugs that inhibit SERT and act as antidepressant and anti-anxiety agents when given to adults). Other changes are congruent with the effects of SSRIs that are given early in the postnatal period, helping to confirm that there is a developmental role for many of the changes that are found in mice with genetically altered SERT — especially when gene–environment and gene–gene effects are taken into account. Many human neurological traits are linked to variations in the gene that encodes the serotonin transporter. Murphy and Lesch describe the phenotypes of mice with altered serotonin-transporter function, emphasizing how this might inform our understanding of the transporter's roles in humans. Mutations resulting in reduced or completely abrogated serotonin-transporter (SERT) function in mice have led to the identification of more than 50 different phenotypic changes, ranging from increased anxiety and stress-related behaviours to gut dysfunction, bone weakness and late-onset obesity with metabolic syndrome. These multiple effects, which can be amplified by gene–environment and gene–gene interactions, are primarily attributable to altered intracellular and extracellular serotonin concentrations during development and adulthood. Much of the human data relating to altered expression o