Mount Sinai lab uncovers epigenetic activity in depression

NEW YORK—Bolstering scientists' understanding of theepigenetic underpinnings of depression, a team of researchers from the IcahnSchool of Medicine at Mount Sinai have identified the epigenetic regulation ofa protein called Rac1, which induces synaptic remodeling in stress disordersand depression.

Currently estimated to have an economic burden of more than$80 billion each year, depression has become tricky to treat due to high ratesof treatment resistance coupled with low probabilities of achieving lastingremission. That high incidence has led to a concerted effort to identify anddevelop new alternative therapeutic approaches on the basis of validateddisease mechanisms, and according to the Mount Sinai researchers, Rac1 reverseddepression-related behaviors in mice—a sign that the protein could be a viabletarget for new therapies for the disease.

"Major depressive disorder affects millions of Americans,many of whom are no longer benefitting from currently available treatments,"says Sam Golden, a graduate student at Mount Sinai and first author on a paper thathe and his colleagues recently published in an advance online issue of Nature Medicine. "There is a significantunmet need for new drug targets for treatment-resistant depression and forbetter understanding of the epigenetic underpinnings of this disease."

Historically, depression treatment strategies have focusedon the monoamine hypothesis of depression, a biological hypothesis stating thatdepression is caused by the underactivity in the brain of monoamines such asdopamine, serotonin and norepinephrine. But more recent work suggests that theneuropathology of depression is stratified across a number of biologicaldomains such as inflammatory cytokines, neurotrophic factors and glutamate.These different systems have a common mechanism in that they all robustlyregulate excitatory synaptic structure and have been shown to play a part inthe etiology of depression and anxiety-like behavior.

In 2011, Mount Sinai researcher Daniel J. Christoffelpublished a study in Nature ReviewsNeuroscience ("Structural and synaptic plasticity in stress-relateddisorders") that highlighted the effects of stress on the structure andfunction of neurons within the mesocorticolimbic brain systems known toregulate mood and motivation. That finding sparked the research team's currentstudy, "Epigenetic regulation of RAC1 induces synaptic remodeling in stressdisorders and depression."

In the new study, Scientists found that Rac1 was diminishedin mouse brains after experiencing a chronic stressor, and in the postmortembrains of humans with major depressive disorder. By manipulating the expressionof Rac1, they were able to control the depressive response in mice.

"We started probing the known regulators of synapticstructure, things that might have driven our earlier findings in 2011," saysDr. Scott Russo, assistant professor of neuroscience at the Graduate School ofBiomedical Sciences at Mount Sinai. "We think our data makes a good argumentfor the epigenetic cause of depression, an experiential cause. Epigenetics isthe study of things that control your genome that are above the genome, not inthe genetic sequence itself. We found in mouse models that there are individualdifferences in how the epigenome expresses itself in response to stress. Themouse data clearly argues that stress can cause changes in the epigenome andreally guide how the animal behaves and responds."

Using a mouse model that Russo and his colleagues repeatedlysubjected to "bouts of social defeat," they evaluated them 48 hours later toidentify any changes in gene expression in the nucleus accumbens (NAc), areward center in the brain. They found that Rac1 was significantly diminished,or downregulated, in the brains of mice for 35 days after the chronic socialdefeat-stress ended.

"We basically used a bully model," Russo explains. "Wescreened for and used a certain strain of mouse that is known to be particularlyaggressive and dominant. For about five minutes a day, we took an experimentalmouse who was docile, and introduced him into the cage. He was considered anintruder by the experimental mouse, who could see and smell the other mouse.This was a slight physical stressor, and at the end of 10 days, the mouseshowed an unwillingness to go out and explore his environment, go into openspaces, interact with cage mates or enjoy social interaction."

Golden next explored the epigenetic regulation of Rac1, orhow the protein is expressed as a result of environmental factors. The researchteam found that social-defeat stress caused changes in chromatin, the structurethat packages DNA, which caused the down-regulation of Rac1.

The team then evaluated postmortem human brain tissue todetermine if their findings in mice were consistent in humans, and discoveredthat Rac1 was downregulated in humans with major depressive disorder as well,and found similar epigenetic changes. In both mice and human brains, Rac1 wasonly normalized in half the subjects treated with antidepressants.

Armed with this knowledge, Golden manipulated Rac1 by eitherknocking out the expression of the protein or over-expressing it by using aprocess called gene transfer, in which Rac1 was encoded onto a modified versionof the herpes virus and infused directly into the NAc of mice. Knocking outRac1 caused social defeat in both the genetically engineered mice and the micethat received the gene transfer. Mice receiving the gene transfer thatoverexpressed an active form of Rac1 were normalized after social defeat,indicating that an infusion of Rac1 may improve neuroplasticity in the brain.

Although Russo notes that this study is among only a few indepression research in which two independent human cohorts and animal modelsvalidated each other, he emphasizes the need to investigate these changes in ahuman population.

"Currently, there is no approval for gene therapy inpsychiatric illness," he says. "We're not ready to be able to do that in ahuman population, and there is a hesitance to go after a therapeutic targetbecause of safety and efficacy issues. I would love to team up with peoplewithin the pharma industry who are knowledgeable about this chemistry to find atherapeutic target for Rac1, to perhaps find a more general modulator for thisphenomenon of synaptic elasticity."

In addition to Christoffel, Golden and Russo, other researchers whoworked on the paper were Mitra Heshmati, Georgia E. Hodes, Jane Magida,Keithara Davis, Michael E. Cahill, Caroline Dias, Efrain Ribeiro, Pamela J.Kennedy, Alfred J. Robison and Javier Gonzalez-Maeso from the FishbergDepartment of Neuroscience and Friedman Brain Institute at Mount Sinai; JessicaL. Ables from the Department of Molecular Biology at Rockefeller University;Rachael L. Neve from the Department of Brain and Cognitive Sciences at theMcGovern Institute of the Massachusetts Institute of Technology; GustavoTurecki from the Depressive Disorders Program at the Douglas Mental Health UniversityInstitute and McGill University in Montréal; and Subroto Ghose and Carol A. Tammingafrom the Department of Psychiatry at the University of Texas SouthwesternMedical Center. Their work received funding from the National Institutes ofMental Health and the Johnson & Johnson International Mental HealthResearch Organization Rising Star Award.