Identifican un gen que podría desempeñar un papel clave en la depresión

Reduced Slc6a15 in Nucleus Accumbens D2-Neurons Underlies Stress Susceptibility

Abstract

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.

• depression
• medium spiny neurons
• nucleus accumbens
• Slc6a15
• social defeat stress

Introduction

Depression is a devastating illness whose complex etiology makes it difficult to treat (Han et al., 2013). One reason for this is that we lack a comprehensive understanding of the vulnerable neuron subtypes and their molecular correlates in depression. Insight into the molecular determinants of depression, in stress-susceptible neuron populations, could provide potential molecules to target for therapeutic treatment of depression. Members of the Slc6 neuronal transporter family, known as the neurotransmitter-sodium-symporter family, are implicated in major depression (Hahn and Blakely, 2007; Bröer, 2013; Rudnick et al., 2014). Recent data suggest that Slc6a15, a neutral amino acid transporter, is a risk gene for major depressive disorder (MDD; Kohli et al., 2011). Homozygote carriers of an A-allele of a single nucleotide polymorphism in a regulatory region of Slc6a15 have a higher risk for depression and depression symptoms compared with those homozygous for the G-allele or heterozygotes (Kohli et al., 2011; Schuhmacher et al., 2013). Homozygote risk allele carriers have decreased Slc6a15 mRNA, display altered hippocampal and anterior cingulate volume, and have changes in hippocampal metabolites (Kohli et al., 2011; Li et al., 2013). However, a recent study (Santarelli et al., 2016) showed that Slc6a15 knock-out mice display reduced anxiety- and depressive-like behavior after stress and that Slc6a15 overexpression in hippocampus resulted in increased anxiety-like behavior. Overall, these studies examining the relationship between Slc6a15 and depression have focused exclusively on the hippocampus as the primary target of investigation. However, Slc6a15 is expressed in a number of brain regions involved in emotional behavior such as the cortex, striatum, amygdala, and ventral tegmental area (Lobo et al., 2006; Hägglund et al., 2013).