Cell-type-specific role for nucleus accumbens neuroligin-2 in depression and stress susceptibility.

TitleCell-type-specific role for nucleus accumbens neuroligin-2 in depression and stress susceptibility.
Publication TypeJournal Article
Year of Publication2018
AuthorsHeshmati M, Aleyasin H, Ménard C, Christoffel DJ, Flanigan ME, Pfau ML, Hodes GE, Lepack AE, Bicks LK, Takahashi A, Chandra R, Turecki G, Lobo MKay, Maze I, Golden SA, Russo SJ
JournalProc Natl Acad Sci U S A
Volume115
Issue5
Pagination1111-1116
Date Published2018 Jan 30
ISSN1091-6490
Abstract

Behavioral coping strategies are critical for active resilience to stress and depression; here we describe a role for neuroligin-2 (NLGN-2) in the nucleus accumbens (NAc). Neuroligins (NLGN) are a family of neuronal postsynaptic cell adhesion proteins that are constituents of the excitatory and inhibitory synapse. Importantly, NLGN-3 and NLGN-4 mutations are strongly implicated as candidates underlying the development of neuropsychiatric disorders with social disturbances such as autism, but the role of NLGN-2 in neuropsychiatric disease states is unclear. Here we show a reduction in NLGN-2 gene expression in the NAc of patients with major depressive disorder. Chronic social defeat stress in mice also decreases NLGN-2 selectively in dopamine D1-positive cells, but not dopamine D2-positive cells, within the NAc of stress-susceptible mice. Functional NLGN-2 knockdown produces bidirectional, cell-type-specific effects: knockdown in dopamine D1-positive cells promotes subordination and stress susceptibility, whereas knockdown in dopamine D2-positive cells mediates active defensive behavior. These findings establish a behavioral role for NAc NLGN-2 in stress and depression; provide a basis for targeted, cell-type specific therapy; and highlight the role of active behavioral coping mechanisms in stress susceptibility.

DOI10.1073/pnas.1719014115
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID29339486
PubMed Central IDPMC5798379
Grant ListFI2 GM117583 / GM / NIGMS NIH HHS / United States
F31 MH105217 / 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
P50 AT008661 / AT / NCCIH NIH HHS / United States
T32 MH096678 / MH / NIMH NIH HHS / United States

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