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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.

SUBMITTER: Golden SA

PROVIDER: S-EPMC3594624 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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

Golden Sam A SA Christoffel Daniel J DJ Heshmati Mitra M Hodes Georgia E GE Magida Jane J Davis Keithara K Cahill Michael E ME Dias Caroline C Ribeiro Efrain E Ables Jessica L JL Kennedy Pamela J PJ Robison Alfred J AJ Gonzalez-Maeso Javier J Neve Rachael L RL Turecki Gustavo G Ghose Subroto S Tamminga Carol A CA Russo Scott J SJ

Nature medicine 20130217 3

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 ...[more]

PMID: 23416703

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Project description:Melatonin, the primary indoleamine hormone of the mammalian pineal gland, is known to have a plethora of neuroregulatory, neuroprotective and other properties. Melatonergic signalling is mediated by its two GPCRs, MT1 and MT2 , which are widely expressed in the mammalian CNS. Melatonin levels and receptor expression often show a decrease during normal ageing, and this reduction may be accelerated in some disease states. Depleted melatonergic signalling has been associated with neuropsychiatric dysfunction and impairments in cognition, memory, neurogenesis and neurorestorative processes. The anticonvulsant and mood stabilizer, valproic acid (VPA), up-regulates melatonin MT1 and/or MT2 receptor expression in cultured cells and in the rat brain. VPA is known to affect gene expression through several mechanisms, including the modulation of intracellular kinase pathways and transcription factors, as well as the inhibition of histone deacetylase (HDAC) activity. Interestingly, other HDAC inhibitors, such as trichostatin A, which are structurally distinct from VPA, can also up-regulate melatonin receptor expression, unlike a VPA analogue, valpromide, which lacks HDAC inhibitory activity. Moreover, VPA increases histone H3 acetylation along the length of the MT1 gene promoter in rat C6 cells. These findings indicate that an epigenetic mechanism, linked to histone hyperacetylation/chromatin remodelling and associated changes in gene transcription, is involved in the up-regulation of melatonin receptors by VPA. Epigenetic induction of MT1 and/or MT2 receptor expression, in areas where these receptors are lost because of ageing, injury or disease, may be a promising therapeutic avenue for the management of CNS dysfunction and other disorders. LINKED ARTICLES: This article is part of a themed section on Recent Developments in Research of Melatonin and its Potential Therapeutic Applications. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.16/issuetoc.

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

Publications

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

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