Major depression (MD) is a severe, life-threatening and widespread psychiatric disorder. The link between exposure to stressful life events and increased risk for MD has been confirmed in several studies. Transition from stress exposure to MD may be gradual and the degree of individual vulnerability may be explained by genetic predisposition. SLC6A4 is a gene associated with depression that encodes for the serotonin transporter (5-HTT). Within SLC64A, the 5-HTT gene-linked polymorphic region (5-HTTLPR) is of particular medical interest. The 5-HTTLPR is expressed in humans and non-human primates with two alleles, S and L, which are associated with low and high transcriptional activity, respectively. Individuals carrying the S allele are more likely to develop MD following exposure to life stress and to respond poorly to antidepressant treatments.

Here, the authors define a mouse model to understand the influence of 5-HTT on the stress response and susceptibility to depression. Their 5-HTT heterozygous mouse shows a 50% reduction of 5-HTT expression, which recapitulates the 50% reduction of 5-HTT that occurs in humans with the 5-HTTLPR S allele, relative to L allele carriers. Exposure of adult male mice to an ethological model of chronic stress over a period of three weeks led to physiological alterations, including weight gain, hyperthermia and increased corticosterone, which are compatible with changes observed in MD patients. These characteristics were independent of 5-HTT deficiency. However, 5-HTT heterozygous mice experience increased suppression of locomotor activity and an increase in social avoidance. This is similar to the psychomotor disturbances and social withdrawal characteristic of people with MD. Importantly, these behavioral changes reflect the amount of stress experienced: higher stress causes greater depression-like behavioral disorders. Stressed 5-HTT heterozygous mice also show reduced serotonin turnover in the frontal cortex, which was not associated with an additional modulation in 5-HTT protein expression.

This mouse model at least in part recapitulates both the genetic and behavioral changes associated with MD in humans through mutation of 5-HTT. It should prove valuable for subsequent studies to identify the mechanisms by which reduced 5-HTT levels may predispose individuals to develop MD. Further work should reveal the molecular effectors that unbalance serotonin transmission in the frontal cortex and establish a functional link with the depression disorders. These findings may open a new venue of research for therapeutic interventions in depressed 5-HTTLPR S allele carriers who are resistant to treatment.