Serotonin Transporter Linked Polymorphic Region: From Behavior to Neural Mechanisms

Abstract

The clinical efficacy of selective serotonin reuptake inhibitors that exert their therapeutic action via the serotonin transporter protein (SERT), which is coded by a single gene (SLC6A4), has fueled research over the past 3 decades. The first report on a functional degenerate repeat polymorphic region within SLC6A4 (serotonin-transporter-linked polymorphic region [5HTTLPR]), associated with anxiety-related personality traits (1), made this genetic variant subject to numerous studies in animals, healthy humans, and psychiatric patients. A mechanistic account of how 5-HTTLPR might moderate psychiatric disease was first demonstrated by a study (2) that showed that the less transcriptionally efficient short (S) allele of 5-HTTLPR amplifies depressive symptoms in the presence of environmental adversity. However, despite the overwhelming number of positive reports, subsequent meta-analytical studies have battled over the reality of such a gene-environment interaction in patients. Thus, a collaborative meta-analysis to draw final conclusions has been launched. Similarly, the originally reported association between 5HTTLPR and anxiety-related personality traits has been challenged several times and in its current state is inconclusive at best. This lack of robust reproducibility of the original findings has been frustrating to many researchers in the field because it questioned the idea of a simple relationship between behavior and a promising candidate gene for psychiatric illness. However, one might also find it intriguing that an association between a molecular biological feature, such as 5-HTTLPR, and a phenomenologically operationalized psychiatric nosology or a psychological construct based on subjective ratings has been found in the first place, given the absence of any biological criterion within their definitions. Genes do not code for psychopathology or personality, but for proteins that may have a direct impact on cell function. Therefore, an intermediate phenotype approach (3) was developed using genetic data as independent variables and imaging measures as dependent variables. This research strategy aimed to establish a more biologically meaningful relationship between a psychiatric risk gene and psychopathology by measuring neural circuit function instead of psychopathology itself. An important reason for this procedure was that behavioral genetics has taught us that changes in brain function related to genetic variation may or may not result in behavioral readouts. Initial studies were conducted primarily in healthy control subjects because of the suspected biological heterogeneity of patient samples and disease-related epiphenomena that might affect neural circuit function (e.g., medication, highly variable symptoms, social deprivation), among other reasons. This research strategy was intended to enable the development of novel and more complex disease models