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

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 from Slc6a15‐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. The neutral amino acid transporter SLC6A15 has been linked to psychiatric disorders, but the functional mechanisms are still unresolved. Using WT and Slc6a15‐KO mouse tissue/primary neurons we show that a lack of this transporter leads to increased mitochondrial function and metabolism, a decreased release probability at glutamatergic synapses and an improved neurite outgrowth. Our data provide further indication that a reduction in SLC6A15 activity may be a promising treatment approach.