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
AuteursHeshmati, M, Aleyasin, H, Menard, 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
Date Published2018 Jan 30

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.