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New Explanation For Depression And Chronic Stress

New Explanation For Depression And Chronic Stress

Researchers identified new mechanism responsible for brain dysfunctions.

torc1, cortex, synapse, redd, depression, stress

Major Depressive Disorder and chronic stress are both characterized by atrophy of neurons and loss of synapses (centers of neurotransmission that deliver neural impulses) in specific brain areas. It’s been recently shown that the prefrontal cortex of subjects with Major Depressive Disorder, analyzed postmortem, contains abnormally low expression levels of a protein called mTORC1, which controls protein synthesis during cell growth and synapses remodeling.

In line with this, it was also observed that in rats some antidepressants augment mTORC1 levels, and this is associated with increased synapses formation in the prefrontal cortex. But what controls mTORC1 expression in the brain? And more importantly, would it be possible to manipulate mTORC1 levels therapeutically to rescue neuronal function?

Stress and TORC1
In a study just published in Nature Medicine, Ota and colleagues from Yale University have identified a new mechanism that is at least in part responsible for the brain alterations caused by loss of mTORC1. The scientists focused on a gene called REDD1 whose product is known to inhibit mTORC1 function. They found that in individuals that were affected by Major Depressive Disorder, high levels of REDD1 correlated with low mTORC1 expression, suggesting a possible link between these two molecules.

To explore this possibility the researchers turned to animal models of stress. They first observed that REDD1 was significantly induced in the prefrontal cortex of rats either exposed to chronic stress, or treated with adrenal glucocorticoids to mimic stress, which also determined a decrease in the number of synapses. Moreover, REDD1 induction was associated with inhibition of mTORC1 activity, in particular of signaling mechanisms that promote protein synthesis necessary for synapses formation and function.

Stress resistant mice
To confirm these findings, the scientists examined the response to chronic stress of knockout (KO) mice lacking REDD1. They demonstrated that while normal mice challenged with chronic stress adopted typical behaviors such as for example anhedonia (decrease sucrose consumption), and showed inhibition of mTORC1-dependent protein synthesis and decreased number of synapses, KO mice did not present any of these features and were resistant to stress.

On the other hand, when REDD1 expression was increased in the prefrontal cortex of rats, the animals assumed an anxiogenic behavior, as measured through several established stress tests, together with loss of cortical synapses and block of mTORC1 activity.

New treatment
All together these experimental results demonstrate that REDD1 lies upstream of mTORC1 in Prefrontal cortex neurons, and its induction by stress leads to mTORC1 inhibition and neuronal atrophy. The value of this work lies in the identification of a new mechanism by which chronic stress causes brain dysfunctions, which is probably involved also in the corresponding alterations observed in Major Depressive Disorder.

This opens interesting possibilities from a therapeutic point of view, because future drugs that oppose REDD1 expression and/or function will enhance mTORC1 activity, and promote synapses formation and integrity, and thus represent new potential treatment options for chronic stress effects and depressive disorders.


References:

Ota KT, Liu RJ, Voleti B, Maldonado-Aviles JG, Duric V, Iwata M, Dutheil S, Duman C, Boikess S, Lewis DA, Stockmeier CA, Dileone RJ, Rex C, Aghajanian GK, & Duman RS (2014). REDD1 is essential for stress-induced synaptic loss and depressive behavior. Nature medicine PMID: 24728411

Photo: Steve Snodgrass
torc1, cortex, synapse, redd, depression, stress

This post was written by Agnese Mariotti:
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