Reduced Slc6a15 in Nucleus Accumbens D2-Neurons Underlies Stress Susceptibility
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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.
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Stress susceptibility is recapitulated by decreasing Slc6a15 specifically in D2-MSNs.
“In mice susceptible to CSDS, Slc6a15 is decreased selectively in D2-MSNs and stress susceptibility is recapitulated by decreasing Slc6a15 specifically in D2-MSNs [136].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [136]
In mice susceptible to CSDS, Slc6a15 is decreased selectively in D2-MSNs.
“In mice susceptible to CSDS, Slc6a15 is decreased selectively in D2-MSNs and stress susceptibility is recapitulated by decreasing Slc6a15 specifically in D2-MSNs [136].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [136]
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The molecular and cellular mechanisms of depression: a focus on reward circuitry
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- Authors
- Chandra, R., Francis, T. C., Nam, H., Riggs, L. M., Engeln, M., Rudzinskas, S., Konkalmatt, P., Russo, S. J., Turecki, G., Iniguez, S. D., & Lobo, M. K.
- Affiliations
- University of Maryland, Baltimore (US)
- George Washington University (US)
- Icahn School of Medicine at Mount Sinai (US)
- Douglas Mental Health University Institute (CA)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2017-06-02
- Volume
- 37
- Issue
- 27
- Pages
- 6527-6538
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC5511883
- OpenAlex
- W2621014178
- Cited by
- 49
- References
- 40
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 6 · 2023: 6 · 2022: 4 · 2021: 7 · 2020: 7 · 2019: 8 · 2018: 3 · 2017: 2
- FWCI
- 2.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health
- National Institute of Mental Health (R01MH090264, R01MH106500)
- National Institute of General Medical Sciences (SC2GM109811, R25GM055036)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- SLC6A15, neutral amino acid transporter, nucleus accumbens, medium spiny neurons, chronic social defeat stress, stress vulnerability, major depressive disorder, depression, ventral striatum, social interaction, gene expression reduction, gene overexpression
- MeSH terms
- Animals, Behavior, Animal, Disease Susceptibility, Dominance-Subordination, Male, Mice, Inbred C57BL, Mice, Transgenic, Nucleus Accumbens, Social Behavior, Stress, Psychological, Receptors, Dopamine D2, Amino Acid Transport Systems, Neutral, Mice, Dopaminergic Neurons
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