杏吧原创

Could preventing the brain shrinkage associated with depression be as simple as blocking a protein?

Post-mortem analysis of brain tissue has shown that the dendrites that relay messages between neurons are more shrivelled in people with severe depression than in people without the condition. This atrophy could be behind some of the symptoms of depression, such as the inability to feel pleasure. As a result, drugs that help repair the neuronal connections, like ketamine, are under investigation.

But how this shrinkage occurs has remained a mystery, limiting researchers鈥� ability to find ways of stopping it.

at Yale University wondered whether a protein called REDD1, which was recently shown to reduce myelin, the fatty material that protects neurons, was the key.

To find out, his team bred rats unable to produce REDD1 and exposed them to a prolonged period of unpredictable stress. In normal rats, this stress resulted in depressive-like behaviour and brain shrinkage, but Duman鈥檚 rats were unaffected.

Stressed-out rats

In contrast, rats engineered to overproduce REDD1 became depressed and had brain shrinkage, even without being stressed.

What鈥檚 more, injecting normal rats with a stress hormone boosted levels of REDD1 in the brain. Giving them a drug that blocked the production of stress hormones stopped them producing the protein, even when they were externally stressed.

Taken together, the experiments show that REDD1 is necessary to produce the brain shrinkage seen in stressed rats, and that stress hormones are involved in its production 鈥� offering a possible way to prevent the shrinkage.

Finally, Duman鈥檚 team looked for the protein in post-mortem brain tissue from people who had depression and those who didn鈥檛. They found that those who had depression had more REDD1 than those who didn鈥檛.

Ketamine boost

Duman thinks that REDD1 causes brain shrinkage by inhibiting the production of another protein called mTORC1. mTORC1 enables the production of a substance that brain cells use to repair themselves. Earlier work by the group showed that ketamine boosted the levels of mTORC1, providing one explanation for its antidepressant affects.

But if REDD1 is behind the reduction in mTORC1, targeting it directly could be a good treatment strategy, says Duman.

鈥淎cute stress is a normal part of life, and you bounce back and that鈥檚 fine,鈥� says at the University of New South Wales in Sydney, Australia, who is studying ketamine as a treatment for depression. 鈥淏ut the longer you鈥檙e depressed the more likely you are to have shrinkage in the brain. This study is teasing out what are the molecular pathways by which stress translates to shrinkage of brain cells.鈥�

鈥淏ut knowing the complexity of humans, it doesn鈥檛 mean this is the whole story,鈥� says Loo.

Journal reference: Nature Medicine,