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SLC6A15, social defeat, behavior, GluR1, hippocampus, emotional behavior
Abstract:
Major depression is a multifactorial disease, involving both
environmental and genetic risk factors. Recently, SLC6A15 - a neutral
amino acid transporter mainly expressed in neurons - was proposed as a
new candidate gene for major depression and stress vulnerability. Risk
allele carriers for a single nucleotide polymorphism (SNP) in a SLC6A15
regulatory region display altered hippocampal volume, glutamate levels,
and hypothalamus-pituitary-adrenal axis activity, all markers associated
with major depression. Despite this genetic link between SLC6A15 and
depression, its functional role with regard to the development and
maintenance of depressive disorder is still unclear. The aim of the
current study was therefore to characterize the role of mouse slc6a15 in
modulating brain function and behavior, especially in relation to stress
as a key risk factor for the development of mood disorders. We
investigated the effects of slc6a15 manipulation using two mouse models,
a conventional slc6a15 knock-out mouse line (SLC-KO) and a
virus-mediated hippocampal slc6a15 overexpression (SLC-OE) model. Mice
were tested under basal conditions and following chronic social stress.
We found that SLC-KO animals displayed a similar behavioral profile to
wild-type littermates (SLC-WT) under basal conditions. Interestingly,
following chronic social stress SLC-KO animals showed lower levels of
anxiety-and depressive-like behavior compared to stressed WT
littermates. In support of these findings, SLC-OE animals displayed
increased anxiety-like behavior already under basal condition. We also
provide evidence that GluR1 expression in the dentate gyrus, but not
GluR2 or NR1, are regulated by slc6a15 expression, and may contribute to
the difference in stress responsiveness observed between SLC-KO and
SLC-WT animals. Taken together, our data demonstrate that slc6a15 plays
a role in modulating emotional behavior, possibly mediated by its impact
on glutamatergic neurotransmission.
