Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression

• Published in: Nature medicine Vol. 19; no. 3; pp. 337 - 344
• Main Authors: Golden, Sam A, Christoffel, Daniel J, Heshmati, Mitra, Hodes, Georgia E, Magida, Jane, Davis, Keithara, Cahill, Michael E, Dias, Caroline, Ribeiro, Efrain, Ables, Jessica L, Kennedy, Pamela J, Robison, Alfred J, Gonzalez-Maeso, Javier, Neve, Rachael L, Turecki, Gustavo, Ghose, Subroto, Tamminga, Carol A, Russo, Scott J
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2013; Nature Publishing Group
• Subjects: 631/378/1689/1414; 631/378/1689/1831; 631/378/2584; 631/378/2591; Actin Depolymerizing Factors - metabolism; Animals; Antidepressive Agents, Tricyclic - pharmacology; Behavior, Animal; Biomedicine; Cancer Research; Care and treatment; Dendritic Spines - pathology; Depressive Disorder, Major - genetics; Depressive Disorder, Major - metabolism; Depressive Disorder, Major - pathology; Diagnosis; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Gene expression; Gene Expression Profiling; Gene therapy; Health aspects; Histones - metabolism; Humans; Imipramine - pharmacology; Infectious Diseases; Major depressive disorder; Male; Medical treatment; Mental depression; Metabolic Diseases; Mice; Mice, Inbred C57BL; Molecular Medicine; Molecular Sequence Data; Neurosciences; Nucleus Accumbens - metabolism; Plasticity; Promoter Regions, Genetic; Promoters (Genetics); rac1 GTP-Binding Protein - genetics; rac1 GTP-Binding Protein - metabolism; Rodents; Social Behavior; Stress; Stress Disorders, Traumatic - drug therapy; Stress Disorders, Traumatic - genetics; Stress Disorders, Traumatic - metabolism; Stress Disorders, Traumatic - pathology; Stress, Psychological - drug therapy; Stress, Psychological - genetics; Stress, Psychological - metabolism; Stress, Psychological - pathology; Toxins; Transcription, Genetic; United States
• ISSN: 1078-8956; 1546-170X
• DOI: 10.1038/nm.3090

Chronic stress and depression induce structural and functional plasticity; however, the mechanisms responsible for these alterations remain incompletely characterized. Here Scott J Russo and colleagues demonstrate that the Rac1 promoter is epigenetically modified, and its expression is reduced in the nucleus accumbens of mice after chronic defeat stress and in subjects with major depressive disorders. Reduced Rac1 expression is sufficient to induce depression-related behavior and stubby spine formation in mice. Depression induces structural and functional synaptic plasticity in brain reward circuits, although the mechanisms promoting these changes and their relevance to behavioral outcomes are unknown. Transcriptional profiling of the nucleus accumbens (NAc) for Rho GTPase–related genes, which are known regulators of synaptic structure, revealed a sustained reduction in RAS-related C3 botulinum toxin substrate 1 (Rac1) expression after chronic social defeat stress. This was associated with a repressive chromatin state surrounding the proximal promoter of Rac1. Inhibition of class 1 histone deacetylases (HDACs) with MS-275 rescued both the decrease in Rac1 transcription after social defeat stress and depression-related behavior, such as social avoidance. We found a similar repressive chromatin state surrounding the RAC1 promoter in the NAc of subjects with depression, which corresponded with reduced RAC1 transcription. Viral-mediated reduction of Rac1 expression or inhibition of Rac1 activity in the NAc increases social defeat–induced social avoidance and anhedonia in mice. Chronic social defeat stress induces the formation of stubby excitatory spines through a Rac1-dependent mechanism involving the redistribution of synaptic cofilin, an actin-severing protein downstream of Rac1. Overexpression of constitutively active Rac1 in the NAc of mice after chronic social defeat stress reverses depression-related behaviors and prunes stubby spines. Taken together, our data identify epigenetic regulation of RAC1 in the NAc as a disease mechanism in depression and reveal a functional role for Rac1 in rodents in regulating stress-related behaviors.