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Tomorrow’s Antidepressants: Skip the Serotonin Boost?

Scientists Reverse Depression-Like Behaviors In Mice Without Raising Serotonin Levels

Science Update

New research adds to evidence of potentially better molecular targets in the brain to treat depression and other mental disorders, according to NIMH-funded scientists.

The researchers suggest that imbalances in the activity of an enzyme called GSK3ß may be closer to the root cause of mental illnesses than are low serotonin levels. Serotonin, a brain chemical, is the ultimate target of several current medications that work by indirectly increasing it to relieve symptoms. In preliminary findings, the scientists suggest that GSK3ß might be a more fundamental – and thus, perhaps, better and faster – target for new medications.

In the new study, even when serotonin levels stayed low, the scientists were able to correct abnormal, mental-illness-like behaviors in mice by blocking GSK3ß. When activated, GSK3ß plays a crucial role inside brain cells by sending chemical signals that help regulate cell function – but this activity must occur at the right time and in the right amount for the brain to function properly.

To assess the effects of blocking GSK3ß, the scientists measured anxiety- and depression-like behaviors shown earlier to be linked to low serotonin levels in mice. For example, compared to normal mice, those with low serotonin gave up sooner when held back by their tails and were slower to come out of dark hiding places to explore their surroundings.

These abnormal behaviors were reversed when scientists blocked GSK3ß in mice with low levels of serotonin. The scientists blocked the enzyme with either genetic engineering or a chemical compound. Success with both approaches strengthens the case for GSK3ß's involvement in mental illnesses – and its potential, with further research, as a new target for medications, the researchers say.

More About the Science

Serotonin is one of several neurotransmitters through which brain cells communicate with each other. Abnormalities in the serotonin system are known to occur in depression, bipolar disorder, anxiety disorder, autism, and schizophrenia, for example.

But increasingly abnormalities in the serotonin system appear to be just one part of chains of molecular events that underlie various mental disorders. Recent research reveals that components such as GSK3ß are involved in these chains of events.

In this study, scientists based their experiments on a gene that makes Tph2, another enzyme involved in serotonin production. A variation of that gene has been linked to depression in some people, and in this study, mice genetically engineered with an equivalent mutation in the Tph2 gene had an 80 percent drop in brain serotonin levels.

As serotonin levels dropped, the GSK3ß enzyme went into action, sending chemical signals into brain cells, and the mice developed abnormal behaviors. The scientists corrected the abnormal behaviors not by increasing serotonin levels, as current medications for many mental disorders do, but by blocking the GSK3ß enzyme, instead.

Taken together, the results offer evidence that both the GSK3ß enzyme and the Tph2 gene play a role in some mental disorders.


Beaulieu J-M, Zhang X, Rodriguiz RM, Sotnikova TD, Cools MJ, Wetsel WC, Gainetdinov RR, Caron MG. Role of GSK3ß in behavioral abnormalities induced by serotonin deficiency. Proceedings of the National Academy of Sciences, 105(4):1333-1338. January 29, 2008