A genetic link between inflammation and depression?

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Whilst there are many different cell types in our body, each contains the same DNA. In order to perform their particular roles, the cell types react differently to the DNA’s instructions by controlling when and how much each gene is expressed. There are entire subsets of genes whose only function is to regulate the expression of others. One of these regulators is called eIF4E and it promotes the expression of a subset of “effector” molecules which share similarities in sequence and structure, though not much is known about their roles. Different “effectors” can be active in different cells, and although eIF4E is highly expressed in the brain not much is known yet about its role there.

A team of researchers at the University of Edinburgh decided to investigate the function of eIF4E in the brain, and at the beginning of March reported their exciting findings in the Journal of Neuroscience.

They used a mouse model to characterise the gene’s function, comparing the gene expression within brain cells of wild-type (i.e. “normal”) and eIF4E-defective (i.e. inactive) mice. Between these two mouse types they identified a subset of genes that were differentially expressed, among which were some that are associated with inflammatory responses. This is consistent with the known role of eIF4E in the immune system.

The researchers then hypothesised that the eIF4E defective mice might have a different inflammatory response. To test this, they stimulated the mice with a bacterial inflammatory-agent and recorded their inflammation levels. Compared to the wild-type mice, the eIF4E-defective mice showed a much stronger inflammatory response.

Using a similar strategy, the researchers also investigated a possible link between eIF4E and ‘the happiness molecule’ – serotonin. This hormone controls mood, appetite and sleep, and recently, its links to inflammation and immune response have become a hotly discussed topic within the scientific community. In this study, eIF4E-defective mice were found to have lower levels of serotonin compared to the wild type animals.

This finding about eIF4E’s involvement in inflammation and serotonin led the researchers to what is arguably the most interesting aspect of the study – because serotonin levels are strongly linked to depression, the scientists reasoned that eIF4E’s role in the brain could be to control the genes involved in depression.

To test this, they assessed the eIF4E defective mice with behavioural tests that are commonly used to find indicators of depression. Mice were assessed on their ability to swim, and to wiggle when held by their tail. In both cases, after an initial period of struggle, eIF4E-defective mice remained immobile for longer than their wild-type counterparts – a behaviour typically associated with depression. Similarly, when mice were prompted to eat in a new environment after 24 hours of food restriction, the eIF4E-defective mice took significantly longer to approach the food. The researchers also treated the mice with fluoxetine (aka Prozac), a drug commonly used to treat chronic depression. In the normal mice, this drug improved their scores in the ‘depression tests’ mentioned above. The eIF4E-defective mice on the other hand were unresponsive to the drug, proving that, at least in mice, the drug needs an active form of eIF4E to be of therapeutic value.

Overall, this study strengthens the link between inflammation and depression, and identifies a potential new target to improve treatments. It also provides a possible explanation as to why some people might respond differently to commonly used drugs, and opens the way for new genetic and pharmacological studies on treating chronic depression.

 

This article was written by Benedetta Carbone and edited by Sam Stanfield.

 

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