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Schraut, K.G.* ; Kalnytska, O.* ; Lamp, D. ; Jastroch, M. ; Eder, M.* ; Hausch, F.* ; Gassen, N.C.* ; Moore, S.* ; Nagaraj, N.* ; Lopez, J.P.* ; Chen, A.* ; Schmidt, M.V.*

Loss of the psychiatric risk factor SLC6A15 is associated with increased metabolic functions in primary hippocampal neurons.

Eur. J. Neurosci. 53, 390-401 (2021)

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Major depressive disorder (MDD) is one of the most severe global health problems with millions of people affected, however, the mechanisms underlying this disorder is still poorly understood. Genome-wide association studies have highlighted a link between the neutral amino acid transporter SLC6A15 and MDD. Additionally, a number of preclinical studies support the function of this transporter in modulating levels of brain neurotransmitters, stress system regulation and behavioural phenotypes related to MDD. However, the molecular and functional mechanisms involved in this interaction are still unresolved. Therefore, to investigate the effects of the SLC6A15 transporter, we used hippocampal tissue fromSlc6a15-KO and wild-type mice, together with several in-vitro assays in primary hippocampal neurons. Utilizing a proteomics approach we identified differentially regulated proteins that formed a regulatory network and pathway analysis indicated significantly affected cellular domains, including metabolic, mitochondrial and structural functions. Furthermore, we observed reduced release probability at glutamatergic synapses, increased mitochondrial function, higher GSH/GSSG redox ratio and an improved neurite outgrowth in primary neurons lacking SLC6A15. In summary, we hypothesize that by controlling the intracellular concentrations of neutral amino acids, SLC6A15 affects mitochondrial activity, which could lead to alterations in neuronal structure and activity. These data provide further indication that a pharmacological or genetic reduction of SLC6A15 activity may indeed be a promising approach for antidepressant therapy.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Amino Acid Transport ; Cell Metabolism ; Depression ; Proline; Acid Transporter Slc6a15; Mitochondrial-function; Depression; Brain; Identification; Vulnerability; Extraction; Disorders; Reversal; Behavior

ISSN (print) / ISBN 0953-816X

e-ISSN 1460-9568

Journal European Journal of Neuroscience

Quellenangaben Volume: 53, Issue: 2, Pages: 390-401

Publisher Wiley

Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Diabetes and Obesity (IDO)

Grants Max Planck Innovations