The amino acid transporter SLC6A15 is a regulator of hippocampal neurochemistry and behavior

• Published in: Journal of psychiatric research 2015-09, Vol.68, p.261-269
• Main Authors: Santarelli, Sara, Namendorf, Christian, Anderzhanova, Elmira, Gerlach, Tamara, Bedenk, Benedikt, Kaltwasser, Sebastian, Wagner, Klaus, Labermaier, Christiana, Reichel, Judith, Drgonova, Jana, Czisch, Michael, Uhr, Manfred, Schmidt, Mathias V
• Format: Article
• Language: English
• Subjects: Amino Acid Transport Systems, Neutral - genetics; Amino Acid Transport Systems, Neutral - metabolism; Amino Acid Transport Systems, Neutral - physiology; Animals; Behavior; Behavior, Animal - physiology; Glutamate; Glutamic Acid - metabolism; Hippocampus; Hippocampus - anatomy & histology; Hippocampus - chemistry; Hippocampus - metabolism; Magnetic Resonance Spectroscopy; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Proline - metabolism; Psychiatry; Real-Time Polymerase Chain Reaction; Sensory Gating - physiology; Signal Transduction; Translational psychiatry
• ISSN: 0022-3956; 1879-1379
• DOI: 10.1016/j.jpsychires.2015.07.012

Abstract Although mental disorders as major depression are highly prevalent worldwide their underlying causes remain elusive. Despite the high heritability of depression and a clear genetic contribution to the disease, the identification of genetic risk factors for depression has been very difficult. The first published candidate to reach genome-wide significance in depression was SLC6A15, a neuronal amino acid transporter. With a reported 1,42 fold increased risk of suffering from depression associated with a single nucleotide polymorphism (SNP) in a regulatory region of SLC6A15, the polymorphism was also found to affect hippocampal morphology, integrity, and hippocampus-dependent memory. However, the function of SLC6A15 in the brain is so far largely unknown. To address this question, we investigated if alterations in SLC6A15 expression, either using a full knockout or a targeted hippocampal overexpression, affect hippocampal neurochemistry and consequently behavior. We could show that a lack of SLC6A15 reduced hippocampal tissue levels of proline and other neutral amino acids. In parallel, we observed a decreased overall availability of tissue glutamate and glutamine, while at the same time the basal tone of extracellular glutamate in the hippocampus was increased. By contrast, SLC6A15 overexpression increased glutamate/glutamine tissue concentrations. These neurochemical alterations could be linked to behavioral abnormalities in sensorimotor gating, a key translational endophenotype relevant for many psychiatric disorders. Overall, our data supports SLC6A15 as a crucial factor controlling amino acid content in the hippocampus, thereby likely interfering with glutamatergic transmission and behavior. These findings emphasize SLC6A15 as pivotal risk factor for vulnerability to psychiatric diseases.