title: The amino acid transporter SLC6A15 is a regulator of hippocampal neurochemistry and behavior.
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.
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany. Electronic address: sara_santarelli@psych.mpg.de.
authors.forename: Sara
authors.initials: S
authors.lastname: Santarelli
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Namendorf
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany.
authors.forename: Elmira
authors.initials: E
authors.lastname: Anderzhanova
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany.
authors.forename: Tamara
authors.initials: T
authors.lastname: Gerlach
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Bedenk
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kaltwasser
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Wagner
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany.
authors.forename: Christiana
authors.initials: C
authors.lastname: Labermaier
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Reichel
authors.affiliation: NIDA-IRP/NIH, 333 Cassell Drive, Baltimore, USA.
authors.forename: Jana
authors.initials: J
authors.lastname: Drgonova
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Czisch
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Uhr
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinstr. 2-10, 80804 Munich, Germany.
authors.forename: Mathias V
authors.initials: MV
authors.lastname: Schmidt
mesh_terms: D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000033:anatomy & histology / Q000737:chemistry / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011392:Proline / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D055139:Sensory Gating / Q000502:physiology*; D015398:Signal Transduction
chemical_list: D026921:Amino Acid Transport Systems, Neutral; C508691:Slc6a15 protein, mouse; D018698:Glutamic Acid; D011392:Proline
keywords: Behavior; Glutamate; Hippocampus; Translational psychiatry