Study Links Brain Enzyme with Depression in Mice
> 2/15/2008 12:53:54 PM

Low levels of the neurotransmitter serotonin have been linked to many psychiatric conditions, from mood and anxiety disorders to schizophrenia. Although many medications used to treat these disorders target serotonin specifically, the exact mechanisms by which serotonin helps to regulate mood are not well understood. Recently, a study published in Proceedings of the National Academy of Sciences furthered our understanding of serotonin's role in mental illness. Duke University Medical Center researchers reversed the abnormal behavior of depressed mice without increasing serotonin levels. Instead, they blocked the activity of the enzyme GSK3▀.

The researchers genetically engineered mice to have a variation of the gene forátryptophan hydroxylase 2 (Tph2), another enzyme that aids in the production of serotonin. In a previous study, Duke researchers discovered that human subjects with a similar genetic variation were susceptible to depression. Interestingly, in this study, depressed subjects who had this genetic variation were resistant to SSRIs, antidepressants that raise serotonin levels. In the current study, mice with the Tph2 variation had 80% less serotonin than normal mice and behaved similarly to humans with low serotonin levels. They were slower than their normal counterparts to explore their surroundings, and when they were held by the tail, they were quicker to stop struggling.

Mice with the Tph2 variation had lower serotonin levels, but researchers also observed an increase of GSK3▀ activity in these mice. They used two different methods to block GSK3▀, testing the role played by this enzyme in depression. As one method, they treated the mice with the SSRI drug Prozac and found that the drug both relieved the symptoms of depression, causing the depressed mice to revert to normal behavior, and inhibited GSK3▀ activity. They produced the same results using genetic engineering to deactivate the GSK3▀ enzyme. This indicates that GSK3▀ activity may represent one mechanism through which serotonin levels influence mood and behavior.

The results of this study may allow for a better understanding of the factors that contribute to depression and other psychiatric conditions, and it may also facilitate the development of new medications. Only about 1/3 of patients reach full recovery using a given antidepressant, and medications that directly target the factors underlying depression, such as GSK3▀, may be more effective or faster-acting. Further research should continue to examine the role played by serotonin in psychiatric illness, and as we learn more about the factors underlying these conditions, we will be better prepared to help those who suffer from them.

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