Depression and Social Defeat Stress Are Associated with Inhibitory Synaptic Changes in the Nucleus Accumbens.

TitleDepression and Social Defeat Stress Are Associated with Inhibitory Synaptic Changes in the Nucleus Accumbens.
Publication TypeJournal Article
Year of Publication2020
AuthorsHeshmati M, Christoffel DJ, LeClair K, Cathomas F, Golden SA, Aleyasin H, Turecki G, Friedman AK, Han M-H, Ménard C, Russo SJ
JournalJ Neurosci
Volume40
Issue32
Pagination6228-6233
Date Published2020 Aug 05
ISSN1529-2401
Abstract

Chronic stress in both humans and rodents induces a robust downregulation of neuroligin-2, a key component of the inhibitory synapse, in the NAc that modifies behavioral coping mechanisms and stress resiliency in mice. Here we extend this observation by examining the role of two other inhibitory synapse constituents, vesicular GABA transporter (vGAT) and gephyrin, in the NAc of male mice that underwent chronic social defeat stress (CSDS) and in patients with major depressive disorder (MDD). We first performed transcriptional profiling of vGAT and gephyrin in postmortem NAc samples from a cohort of healthy controls, medicated, and nonmedicated MDD patients. In parallel, we conducted whole-cell electrophysiology recordings in the NAc of stress-susceptible and stress-resilient male mice following 10 d of CSDS. Finally, we used immunohistochemistry to analyze protein levels of vGAT and gephyrin in the NAc of mice after CSDS. We found that decreased vGAT and gephyrin mRNA in the NAc of nonmedicated MDD patients is paralleled by decreased inhibitory synapse markers and decreased frequency of mini inhibitory postsynaptic currents (mIPSC) in the NAc of susceptible mice, indicating a reduction in the number of NAc inhibitory synapses that is correlated with depression-like behavior. Overall, these findings suggest a common state of reduced inhibitory tone in the NAc in depression and stress susceptibility. Existing studies focus on excitatory synaptic changes after social stress, although little is known about stress-induced inhibitory synaptic plasticity and its relevance for neuropsychiatric disease. These results extend our previous findings on the critical role of impaired inhibitory tone in the NAc following stress and provide new neuropathological evidence for reduced levels of inhibitory synaptic markers in human NAc from nonmedicated major depressive disorder patients. This finding is corroborated in stress-susceptible male mice that have undergone chronic social defeat stress, a mouse model of depression, at both the level of synaptic function and protein expression. These data support the hypothesis that reduced inhibitory synaptic transmission within the NAc plays a critical role in the stress response.

DOI10.1523/JNEUROSCI.2568-19.2020
Alternate JournalJ Neurosci
PubMed ID32561672
PubMed Central IDPMC7406280
Grant ListR01 MH104559 / MH / NIMH NIH HHS / United States
R01 MH120637 / MH / NIMH NIH HHS / United States
P50 AT008661 / AT / NCCIH NIH HHS / United States
R56 MH115409 / MH / NIMH NIH HHS / United States
F30 MH100835 / MH / NIMH NIH HHS / United States
T32 MH087004 / MH / NIMH NIH HHS / United States
P50 MH096890 / MH / NIMH NIH HHS / United States
R01 MH114882 / MH / NIMH NIH HHS / United States
R01 MH090264 / MH / NIMH NIH HHS / United States