Reduced Slc6a15 in Nucleus Accumbens D2-Neurons Underlies Stress Susceptibility
J. Neurosci.. 2017-06-02; 37(27): 6527-6538
DOI: 10.1523/jneurosci.3250-16.2017
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Chandra R(1), Francis TC(1), Nam H(1), Riggs LM(1), Engeln M(1), Rudzinskas S(1), Konkalmatt P(2), Russo SJ(3), Turecki G(4), Iniguez SD(5), Lobo MK(6).
Author information:
(1)Department of Anatomy and Neurobiology, University of Maryland School of
Medicine, Baltimore, Maryland 21201.
(2)Division of Renal Diseases and Hypertension, The George Washington University,
Washington, DC 20037.
(3)Fishberg Department of Neuroscience and Friedman Brain Institute, Graduate
School of Biomedical Sciences at the Icahn School of Medicine at Mount Sinai, New
York, New York 10029.
(4)McGill Group for Suicide Studies, Douglas Mental Health University Institute,
McGill University, Montréal, Québec H4H 1R3, Canada, and.
(5)Department of Psychology, University of Texas at El Paso, El Paso, Texas
79968.
(6)Department of Anatomy and Neurobiology, University of Maryland School of
Medicine, Baltimore, Maryland 21201, .
Previous research demonstrates that Slc6a15, a neutral amino acid transporter, is
associated with depression susceptibility. However, no study examined Slc6a15 in
the ventral striatum [nucleus accumbens (NAc)] in depression. Given our previous
characterization of Slc6a15 as a striatal dopamine receptor 2
(D2)-neuron-enriched gene, we examined the role of Slc6a15 in NAc D2-neurons in
mediating susceptibility to stress in male mice. First, we showed that Slc6a15
mRNA was reduced in NAc of mice susceptible to chronic social defeat stress
(CSDS), a paradigm that produces behavioral and molecular adaptations that
resemble clinical depression. Consistent with our preclinical data, we observed
Slc6a15 mRNA reduction in NAc of individuals with major depressive disorder
(MDD). The Slc6a15 reduction in NAc occurred selectively in D2-neurons. Next, we
used Cre-inducible viruses combined with D2-Cre mice to reduce or overexpress
Slc6a15 in NAc D2-neurons. Slc6a15 reduction in D2-neurons caused enhanced
susceptibility to a subthreshold social defeat stress (SSDS) as observed by
reduced social interaction, while a reduction in social interaction following
CSDS was not observed when Slc6a15 expression in D2-neurons was restored.
Finally, since both D2-medium spiny neurons (MSNs) and D2-expressing choline
acetyltransferase (ChAT) interneurons express Slc6a15, we examined Slc6a15
protein in these interneurons after CSDS. Slc6a15 protein was unaltered in ChAT
interneurons. Consistent with this, reducing Slc5a15 selectively in NAc D2-MSNs,
using A2A-Cre mice that express Cre selectively in D2-MSNs, caused enhanced
susceptibility to SSDS. Collectively, our data demonstrate that reduced Slc6a15
in NAc occurs in MDD individuals and that Slc6a15 reduction in NAc D2-neurons
underlies stress susceptibility.SIGNIFICANCE STATEMENT Our study demonstrates a
role for reduced Slc6a15, a neutral amino acid transporter, in nucleus accumbens
(NAc) in depression and stress susceptibility. The reduction of Slc6a15 occurs
selectively in the NAc D2-neurons. Genetic reduction of Slc6a15 induces
susceptibility to a subthreshold stress, while genetic overexpression in
D2-neurons prevents social avoidance after chronic social defeat stress.