Depressed Without Rac1

Science Signaling  26 Mar 2013:
Vol. 6, Issue 268, pp. ec71
DOI: 10.1126/scisignal.2004173

In the chronic social defect stress model of depression, smaller mice are repeatedly confronted with larger, more aggressive mice, which results in the majority of the smaller mice developing social avoidance and anhedonic responses (referred to as “susceptible” mice) and the remaining mice showing resilience. Susceptible mice have an increase in dendritic spines with an “immature” or stubby morphology in medium spiny neurons in the nucleus accumbens. Because the changes in dendritic spine morphology implicate proteins that control cytoskeletal organization, Golden et al. analyzed Rho guanosine triphophatase (GTPase)–related genes and found that the expression of Rac1 was decreased in the nucleus accumbens of susceptible mice, but not resilient mice, an effect that was partially reversed by chronic treatment with the antidepressant imipramine. Genome-wide promoter analysis indicated that the Rac1 promoter in susceptible mice was repressed, as indicated by decreased histone H3 acetylation and increased H3 Lys9 trimethylation (H3K27me3). Local administration of an HDAC inhibitor into the nucleus accumbens of susceptible mice reversed social avoidance behavior and increased Rac1 mRNA abundance. Susceptible mice showed reduced social avoidance after overexpression of a constitutively active form of Rac1 in the nucleus accumbens. In contrast, mice lacking Rac1 or that overexpressed a dominant-negative form of Rac1 in the nucleus accumbens developed social avoidance and anhedonia after a subthreshold microdefeat stress, which involves shorter and fewer exposures to aggressor mice and is designed to measure susceptibility to stress. Mice experiencing chronic social defeat had an increase in immature stubby spines on medium spiny neurons in the nucleus accumbens. The change in stubby spine density in susceptible mice was attenuated by overexpression of constitutively active Rac1 and stubby spine density correlated with social avoidance behavior. Deletion of Rac1 in the nucleus accumbens increased stubby spine density in nonstressed mice and mice subjected to microdefeat stress. Analysis of postmortem nucleus accumbens tissue samples indicated that RAC1 mRNA abundance was lower in individuals with major depressive disorder who were not on medication at their time of death compared with nondepressed individuals and that RAC1 mRNA abundance correlated with H3 acetylation, although not with trimethylation status. In the associated commentary, Duman notes that therapies that target RAC1 signaling could be used to treat major depressive disorders.

S. A. Golden, D. J. Christoffel, M. Heshmati, G. E. Hodes, J. Magida, K. Davis, M. E. Cahill, C. Dias, E. Ribeiro, J. L. Ables, P. J. Kennedy, A. J. Robison, J. Gonzalez-Maeso, R. L. Neve, G. Turecki, S. Ghose, C. A. Tamminga, S. J. Russo, Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression. Nat. Med. 19, 337–344 (2013). [PubMed]

R. S. Duman, Remodeling chromatin and synapses in depression. Nat. Med. 19, 267–268 (2013). [PubMed]