Tiny molecules boost mood

Small molecules may lead to the development of more effective treatments and/or biomarkers in mood disorders

A link between dysregulation of the brain’s serotonin system and psychiatric diseases is well known, yet the underlying molecular mechanisms still remain elusive. Scientists of the “Max Planck – Weizmann Laboratory for Experimental Neuropsychiatry and Behavioral Neurogenetics” for the first time identified a connection between particular molecules (miR135) and two key players in the serotonin system. These findings may pave the way for better understanding of psychiatric diseases that are associated with dysregulation of the serotonin system and may lead to the development of more effective treatments and/or biomarkers.

Scientists of the “Max Planck – Weizmann Laboratory for Experimental Neuropsychiatry and Behavioral Neurogenetics” headed by Alon Chen, Director at the Max Planck Institute of Psychiatry, investigated the brain’s serotonin system. Serotonin is a messenger produced by specialized nerve cells in the brain that affects for instance appetite, pain perception or mood. Dysregulation of the serotonin system is widely associated with depression or anxiety disorders and targeted by most of the available antidepressants.

Alon Chen and his research team investigated the role of microRNAs in nerve cells that produce serotonin. MicroRNAs are very small, non-coding RNA molecules that regulate various cellular activities. For the first time, the team identified a particular microRNA (miR135) which downregulates two proteins that play a key role in serotonin production and the regulation of its activities. The first protein, the serotonin transporter SERT, is the direct target of most commonly used antidepressants. The second protein is the receptor HTR1A which inhibits serotonin-producing nerve cells and has been postulated to be one of the causes for the therapeutic lag that is frequently reported for most serotonergic antidepressants. Decreased activity of both SERT and HTR1A would be expected to increase the serotonin levels in the brain. This effect is consistent with antidepressant action and decreases in depressive symptoms.

Studies using mice revealed a clear upregulation of miR135 after antidepressant administration. Further, genetically modified mouse models either expressing higher or lower levels of miR135 showed major alterations in anxiety- and depression-like behavior as well as in the response to antidepressant treatment. Mice overexpressing miR135 in serotonin-producing nerve cells showed a strong protective effect from the adverse behavioral effects of chronic social stress. In a complementary approach, reduced levels of miR135 caused an increase in anxiety-like behavior and an attenuated response to antidepressants. In line with these data from animal models the scientists found in collaboration with Elisabeth Binder, Director at the Max Planck Institute of Psychiatry, robustly reduced blood levels of miR135 in depressed patients.

“In line with our observations in mice indicating miR135 to be an endogenous regulator of mood and vulnerability to depression, our results suggest miR135 as a possible biomarker for depression state and eventually for response to drug treatment in humans”, states Orna Issler, a former PhD student in Alon Chen’s research team and first author of the current study. These findings may pave the way for better understanding of psychiatric diseases that are associated with the dysregulation of the serotonin system and may lead to the development of more effective treatments and/or biomarkers.

According to the World Health Organization psychiatric diseases such as major depression or anxiety disorders are among the most common health problems worldwide. Psychiatric diseases affect approximately 10% of the population but the underlying mechanisms are only partly understood. About 30 to 40% of patients do not respond to available antidepressants. The other 60 to 70% experience merely partial remission and have to take the drugs for a long period before feeling any effects. In addition, there are many side effects associated with the currently available antidepressants. New and better drugs are clearly needed, an undertaking that requires first and foremost a better understanding of the processes and causes underlying the disorders.