Title | Cell-type-specific role for nucleus accumbens neuroligin-2 in depression and stress susceptibility. |
Publication Type | Journal Article |
Year of Publication | 2018 |
Auteurs | Heshmati, 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 |
Journal | Proc Natl Acad Sci U S A |
Volume | 115 |
Issue | 5 |
Pagination | 1111-1116 |
Date Published | 2018 01 30 |
ISSN | 1091-6490 |
Keywords | Aggression, Animals, Antidepressive Agents, Behavior, Animal, Cell Adhesion Molecules, Neuronal, Cell Line, Depressive Disorder, Major, Disease Models, Animal, Dominance-Subordination, Heterozygote, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, MicroRNAs, Nerve Tissue Proteins, Nucleus Accumbens, Receptors, Dopamine D1, Receptors, Dopamine D2, RNA, Messenger, Social Behavior, Stress, Psychological, Synapses |
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. |
DOI | 10.1073/pnas.1719014115 |
Alternate Journal | Proc. Natl. Acad. Sci. U.S.A. |
PubMed ID | 29339486 |
PubMed Central ID | PMC5798379 |
Grant List | FI2 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 R01 MH106500 / MH / NIMH NIH HHS / United States T32 MH096678 / MH / NIMH NIH HHS / United States |