Serotonin transporter and psychiatric disorders: Listening to the gene

Mood, cognition, and many other physiological functions are modulated by the midbrain raphe serotonin (5-HT) system. By directing the magnitude and duration of postsynaptic receptor-mediated signaling, the 5-HT transporter (5-HTT) plays a crucial role in the integration of 5-HT neurotransmission. Considerable progress has been made in the molecular characterization of the 5-HTT, and research is currently focusing on the organization of 5-HTT gene (SLC6A4, OMIM accession number 182138), on the regulation of 5-HTT expression, on alterations in expression because of allelic variation in gene transcription, on structure-activity relationships of the 5-HTT protein, and on mechanisms of 5-HT and ion translocation. In the psychobiological dimension, it is becoming increasingly evident that inadequate adaptive responses to environmental stressors, in conjunction with predisposing genes like the 5-HTT, contribute to the etiopathogenesis of behavioral and psychiatric disorders. A polymorphism in the regulatory region of the 5-HTT gene is associated with anxiety-and depression-related personality traits, and preliminary studies suggest that it influences the risk to develop affective disorders, alcohol dependence, and late-onset dementias. Finally, transgenic strategies are gaining momentum for the validation of the concept of the 5-HTT gene as a susceptibility locus for emotional instability (neuroticism) and psychiatric disorders. This approach addresses the pertinent question: to what extent does targeted disruption of the 5-HTT gene affect biochemistry, electrophysiology, and pharmacology of the 5-HT system and modulate neural development and synaptic plasticity? It may also provide a model system that facilitates the dissection of successive events that lead to disease states as well as to the testing of novel therapeutic concepts.