title: 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.
authors: Fishberg Department of Neuroscience and Friedman Brain Institute, Graduate School of Biomedical Sciences at the Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors: Sam A
authors: SA
authors: Golden
authors: Daniel J
authors: DJ
authors: Christoffel
authors: Mitra
authors: M
authors: Heshmati
authors: Georgia E
authors: GE
authors: Hodes
authors: Jane
authors: J
authors: Magida
authors: Keithara
authors: K
authors: Davis
authors: Michael E
authors: ME
authors: Cahill
authors: Caroline
authors: C
authors: Dias
authors: Efrain
authors: E
authors: Ribeiro
authors: Jessica L
authors: JL
authors: Ables
authors: Pamela J
authors: PJ
authors: Kennedy
authors: Alfred J
authors: AJ
authors: Robison
authors: Javier
authors: J
authors: Gonzalez-Maeso
authors: Rachael L
authors: RL
authors: Neve
authors: Gustavo
authors: G
authors: Turecki
authors: Subroto
authors: S
authors: Ghose
authors: Carol A
authors: CA
authors: Tamminga
authors: Scott J
authors: SJ
authors: Russo
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001522:Behavior, Animal; D049229:Dendritic Spines / Q000473:pathology*; D003865:Major Depressive Disorder / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D006657:Histones / Q000378:metabolism; D006801:Humans; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009714:Nucleus Accumbens / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012919:Social Behavior; D040921:Stress Disorders, Traumatic / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013315:Stress, Psychological / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014158:Transcription, Genetic; D020830:rac1 GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism*
chemical_list: D051339:Actin Depolymerizing Factors; D000929:Antidepressive Agents, Tricyclic; D006657:Histones; D020830:rac1 GTP-Binding Protein; D007099:Imipramine