by only a single episode of stress, indicating that only prolonged stressors that induce depressionare capable of downregulating Rac1.The scientists note that chronic stress in the mice caused epigenetic changes in chromatin that ledto Rac1 downregulation.They were able to control the depressive response to chronic stress to some extent by chronicantidepressant treatment. Histone deacetylase (HDAC) inhibitors were "extremely effective in both normalizing the reduction in Rac1 and also promoting antidepressant responses," Dr. Russotold
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
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 theindividuals with MDD who were taking antidepressants at the time of death, Rac1 expressionwas not restored to the levels seen in control participants, "suggesting a need for more directRAC1-targeting strategies to achieve therapeutic effects," the authors write."Currently, there aren't any approved drugs or even experimental drugs that target Rac1 that aresafe 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 andrestructuring 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 doesthis, 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 notinvolved in the research, said the study "is exquisitely well done. The researchers did anexcellent 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 studiedRac1, 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 Rac1has 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 smallGTPases such as Rac1 have a tremendous role as modulators of these processes. However, we