The serotonin transporter gene and functional and pathological adaptation to environmental variation across the life span

In analogy with the accepted view that behaviour is shaped by gene × environment (G × E) interactions, G × E studies are exponentially increasing in the field of psychiatry. Whereas research was primarily driven by the premature view that negative environmental stimuli can trigger psychopathology in those subjects that are genetically predisposed, a closer look at the available data shows that G × E interactions are much more complex than initially thought. Here, we discuss G × E studies focussing on serotonin transporter (5-HTT, SERT, SLC6A4) gene variation in humans, monkeys, and rodents. Recent studies, across species, confirm the theorized ‘for-better-and-for-worse’ effect of low activity serotonin transporter genotypes. In addition, while 5-HTT × E interactions were thought to take place in early life, recent evidence illustrates that these interactions are also manifested in adulthood. Therefore, we discuss data based on 5-HTT × E interactions, and propose a model in which predictive adaptive responses (PARs), as shaped by early life 5-HTT × E interactions, shape responses to environmental challenges in later life, i.e. reflecting 5-HTT × E × E interactions.

► Serotonin transporter gene variation in humans, monkeys and rodents increases sensitivity to environmental stimuli, ‘for-better-and-for-worse’. ► This environmental sensitivity is expressed both in early life and adulthood. ► This environmental sensitivity also shapes predictive adaptive responses, determining the window of adaptive responsivity to environmental stimuli. ► The underlying mechanisms may involve changes in corticolimbic circuits, HPA-axis function, and epigenetic modifications.