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

Sam A. Golden, Daniel J. Christoffel, Mitra Heshmati, Georgia E. Hodes, Jane Magida, Keithara Davis, Michael E. Cahill, Caroline Dias, Efrain Ribeiro, Jessica L. Ables, Pamela J. Kennedy, Alfred J. Robison, Javier Gonzalez-Maeso, Rachael L. Neve, Gustavo Turecki, Subroto Ghose, Carol A. Tamminga, Scott J. Russo

Research output: Contribution to journalArticlepeer-review

253 Scopus citations


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.

Original languageEnglish
Pages (from-to)337-344
Number of pages8
JournalNature Medicine
Issue number3
StatePublished - Mar 2013


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