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Glutamate, Hippocampus, Translational psychiatry, 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. (C) 2015 Published by
Elsevier Ltd.
