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Potential Cause of Depression Identified

Findings Have 'Enormous Therapeutic Potential,' Researchers Say


Megan Brooks Feb 19, 2013 A protein involved in synaptic structure has been identified as a potential cause of depression, a finding that according to researchers has "enormous therapeutic potential for the development of biomarkers and novel therapeutic agents." Investigators at the Mount Sinai School of Medicine in New York City found decreased expression of Rac1 in the postmortem brains of people with major depressive disorder (MDD) and in mice subjected to chronic stress. They were able to control the depressive response in mice by manipulating the expression of Rac1.

Dr. Scott Russo "Our study is among only a few in depression research in which 2 independent human cohorts and animal models validate each other. Rac1 has enormous therapeutic potential, and I look forward to investigating it further," study investigator Scott Russo, PhD, said in a statement. The research was published online February 17 in Nature Medicine. Looking for Drug Targets Rac1 is a small Rho GTPase protein involved in modulating synaptic structure. "There is a hypothesis that depression and stress disorders are caused by a restructuring of brain circuitry," Dr. Russo explained in an interview with Medscape Medical News. The scientists subjected mice to repeated bouts of social stress and then evaluated the animals for changes in gene expression in the nucleus accumbens (NAc), the brain's reward center. The researchers found that expression of Rac1 was significantly downregulated in the brains of mice for at least 35 days following the end of the chronic social stressor. Rac1 was not affected

by only a single episode of stress, indicating that only prolonged stressors that induce depression are capable of downregulating Rac1. The scientists note that chronic stress in the mice caused epigenetic changes in chromatin that led to Rac1 downregulation. They were able to control the depressive response to chronic stress to some extent by chronic antidepressant treatment. Histone deacetylase (HDAC) inhibitors were "extremely effective in both normalizing the reduction in Rac1 and also promoting antidepressant responses," Dr. Russo told Medscape Medical News. "What we think is happening is that chronic stress leads to a lasting change in the ability of our genes to transcribe this RAC1 gene, and if you target the epigenome, you can reverse that loss of Rac1 and promote synapses and more normal healthy responses," he said. As in the mice, Rac1 expression was also strongly downregulated in the NAc in postmortem brains of patients with MDD, who displayed similar epigenetic changes. In most of the individuals with MDD who were taking antidepressants at the time of death, Rac1 expression was not restored to the levels seen in control participants, "suggesting a need for more direct RAC1-targeting strategies to achieve therapeutic effects," the authors write. "Currently, there aren't any approved drugs or even experimental drugs that target Rac1 that are safe and effective," Dr. Russo said. "It would be nice if we could team up with some chemists or pharma and figure out if there are some safe and effective Rac activators." However, there are caveats to that, he said. "It might be difficult to target Rac specifically, because it is involved in cell proliferation and restructuring so it may be difficult to get a compound that doesn't cause cancer. It might be better to screen for targets that more generally regulate synaptic plasticity. Ketamine is a drug that does this, and there is huge interest in ketamine" in depression, Dr. Russo said. Experts Weigh In Commenting on the findings for Medscape Medical News, David Dietz, PhD, assistant professor of pharmacology and toxicology, State University of New York at Buffalo, who was not involved in the research, said the study "is exquisitely well done. The researchers did an excellent job of translating their findings in the rodent model to the human condition." Maria V. Tejada-Simon, PhD, who also was not involved in this research but who has studied Rac1, noted that her group has been "highlighting the importance of Rac1 in the brain in general, and in psychiatric diseases in particular, for a while now. Therefore, I am not surprised that Rac1 has been found to be also associated to stress disorders and depression." "Mood disorders have been linked to changes in synaptic structure, and it is certain that small GTPases such as Rac1 have a tremendous role as modulators of these processes. However, we

need to understand that alterations in Rac1 signaling are not likely to be the primary defect in mood disorders. "Thus, targeting Rac1 to moderate clinical symptoms (while there is potential for a translational approach there) has to be done very carefully, given the broad role of Rac1 in many cellular functions involving the actin cytoskeleton," said Dr. Tejada-Simon, assistant professor of pharmacology and adjunct assistant professor of biology and psychology at University of Houston College of Pharmacy in Texas. "The highlight of this research is in identifying a possible mechanism by which we can study pathways that are involved in remodeling of the brain; we might be able to find something a little bit more specific down the line," Dr. Dietz said. He noted that Rac1 has also been linked to addiction. "It's well known that there is comorbidity between depression and addiction, that one may lead to the other, so there seems to be something fundamentally related between Rac1 and these 2 psychiatric disease states." The research was supported by the National Institute of Mental Health and the Johnson and Johnson International Mental Health Research Organization Rising Star Award (presented to Dr. Russo). The other authors, Dr. Tejada-Simon, and Dr. Dietz have disclosed no relevant financial relationships. Nat Med. Published online February 17, 2013. Abstract

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