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

Abstract

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.

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Figure 1: Chronic social defeat stress decreases Rac1 mRNA expression in the NAc of susceptible but not resilient mice.
Figure 2: Epigenetic regulation of Rac1 after chronic social defeat stress.
Figure 3: Epigenetic regulation of RAC1 mRNA expression in subjects with MDD.
Figure 4: Rac1 expression in the NAc modulates stress-related behavior in mice.
Figure 5: Expression of constitutively active Rac1 (HSV-RacCA) in the NAc prevents chronic social defeat stress–induced stubby spine formation.
Figure 6: Conditional deletion of Rac1 in NAc of Rac1flox/flox mice increases stubby and thin dendritic spines.

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Acknowledgements

We thank Y. Zeng (University of Cincinnati) for providing Rac1flox/flox mice. This research was supported by US National Institute of Mental Health grant R01 MH090264, the Johnson and Johnson International Mental Health Research Organization Rising Star Award (S.J.R.), US National Institute of Mental Health grants P50 MH66172 and P50MH096890 (C.A.T.) and US National Institutes of Health grant T32 GM062754 (K.D.).

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S.A.G. and S.J.R. contributed to study design, data collection, analysis and writing. D.J.C., M.H., G.E.H., J.M., K.D., M.E.C., C.D., E.R., A.J.R., P.J.K. and J.L.A. contributed to data collection. J.G.-M. contributed to data analysis. R.L.N. contributed to viral design and packaging. G.T., S.G. and C.A.T. collected human brain samples and contributed to data analysis.

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Correspondence to Scott J Russo.

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Golden, S., Christoffel, D., Heshmati, M. et al. Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression. Nat Med 19, 337–344 (2013). https://doi.org/10.1038/nm.3090

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