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

Significance Although mutations in the neuroligin-3 and neuroligin-4 genes are implicated in autism syndromes, very little is known about the contribution of neuroligin-2 to neuropsychiatric disease states. We report a decrease in neuroligin-2 gene expression in the postmortem nucleus accumbens (NAc) of depressed patients. Reverse translation of this finding in chronic social defeat stress, an animal model of depression that enables investigation of both susceptibility and resiliency mechanisms, uncovers an important functional role for NAc neuroligin-2 in stress susceptibility. We detail a cell-type-specific role for NAc neuroligin-2 in modulating social avoidance behavior and dominance behaviors important for resiliency. Together, these findings describe a role for NAc neuroligin-2 in depression and chronic stress behaviors. 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.

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