In conclusion, the above presented results from human genetics, gene expression, volumetric imaging, spectroscopy, and a mouse model of chronic stress all support the notion that lower SLC6A15 expression, especially in the hippocampus, could increase an individual’s stress susceptibility by altering neuronal integrity and excitatory neurotransmission in this brain region. Recently, the prokaryotic leucine transporter homologue (LeuTaa) of SLC6A15 has been crystallized from Aquifex aeolicus and was shown to bind tricyclic antidepressant drugs that can directly block leucine transport by closing the molecular gate for the substrate in a non-competitive manner (Zhou et al., 2007). Due to the high degree of phylogenetic conservation of the antidepressant binding site, these drugs probably also bind to the human transporter. Because SLC6A15 appears amenable to drug targeting, our results may incite the discovery of a novel class of antidepressant drugs.
