SNORD90 induces glutamatergic signaling following treatment with monoaminergic antidepressants
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eLife assessment
This is an important study that uncovers a new molecular pathway that links traditional monoaminergic antidepressants with regulation of glutamate neurotransmission. The data provided for the model are convincing and demonstrate the pathway in human plasma and brain, mouse brain, and cultured cells, using the relative strengths of each system. The work will be of interest to psychiatrists studying depression as well as basic neurobiologists interested in monoamine signaling in the brain.
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Abstract
Pharmacotherapies for the treatment of major depressive disorder were serendipitously discovered almost seven decades ago. From this discovery, scientists pinpointed the monoaminergic system as the primary target associated with symptom alleviation. As a result, most antidepressants have been engineered to act on the monoaminergic system more selectively, primarily on serotonin, in an effort to increase treatment response and reduce unfavorable side effects. However, slow and inconsistent clinical responses continue to be observed with these available treatments. Recent findings point to the glutamatergic system as a target for rapid acting antidepressants. Investigating different cohorts of depressed individuals treated with serotonergic and other monoaminergic antidepressants, we found that the expression of a small nucleolar RNA, SNORD90 , was elevated following treatment response. When we increased Snord90 levels in the mouse anterior cingulate cortex (ACC), a brain region regulating mood responses, we observed antidepressive-like behaviors. We identified neuregulin 3 ( NRG3 ) as one of the targets of SNORD90 , which we show is regulated through the accumulation of N 6 -methyladenosine modifications leading to YTHDF2-mediated RNA decay. We further demonstrate that a decrease in NRG3 expression resulted in increased glutamatergic release in the mouse ACC. These findings support a molecular link between monoaminergic antidepressant treatment and glutamatergic neurotransmission.
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eLife assessment
This is an important study that uncovers a new molecular pathway that links traditional monoaminergic antidepressants with regulation of glutamate neurotransmission. The data provided for the model are convincing and demonstrate the pathway in human plasma and brain, mouse brain, and cultured cells, using the relative strengths of each system. The work will be of interest to psychiatrists studying depression as well as basic neurobiologists interested in monoamine signaling in the brain.
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Reviewer #1 (Public Review):
The authors of this manuscript are interested in identifying the molecular mechanisms underlying antidepressant action. Though most antidepressants target the serotonin system, regulation of glutamate neurotransmission has been associated with rapid treatment response. Here the authors find that monoaminergic targeted antidepressants are associated in some patients with expression of a small nucleolar RNA that they go on to show results in alterations to glutamate neurotransmission in a mouse model. These data offer a molecular mechanism that can link traditional monoaminergic targeted antidepressants with glutamatergic regulation and could offer a new way to estimate the efficacy of these drugs.
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Reviewer #2 (Public Review):
The molecular mechanisms by which monoaminergic antidepressants exert their therapeutic effects are unknown. An emerging hypothesis in this regard is that these antidepressants work by modulating the glutamatergic system, yet the precise links remain unclear. In this manuscript, Lin et al. describe one such link. First, they observe that the small nucleolar RNA (snoRNA), SNORD90 is consistently elevated following antidepressant treatments in peripheral blood samples, in postmortem brain samples of individuals that received antidepressant treatments, mouse models of depression, and in induced neurons treated with antidepressants in culture. To test whether the elevation of SNORD90 could be significant for antidepressive-like behaviors, the authors perform bilateral injections of viral vectors carrying either …
Reviewer #2 (Public Review):
The molecular mechanisms by which monoaminergic antidepressants exert their therapeutic effects are unknown. An emerging hypothesis in this regard is that these antidepressants work by modulating the glutamatergic system, yet the precise links remain unclear. In this manuscript, Lin et al. describe one such link. First, they observe that the small nucleolar RNA (snoRNA), SNORD90 is consistently elevated following antidepressant treatments in peripheral blood samples, in postmortem brain samples of individuals that received antidepressant treatments, mouse models of depression, and in induced neurons treated with antidepressants in culture. To test whether the elevation of SNORD90 could be significant for antidepressive-like behaviors, the authors perform bilateral injections of viral vectors carrying either SNORD90 or scrambled controls into the mouse cg1/2 and show that overexpression of SNORD90 reduces anxiety and depressive-like behaviors. Using in-silico analysis of base complementarity, the authors predict that the growth factor, neuregulin 3 (NRG3), could be a potential target of SNORD90, and they then validate this prediction by directly showing that SNORD90 overexpression results in the reduction of NRG3 in human neural progenitor cells, whereas knockdown of SNORD90 upregulates NRG3. The authors then show that the binding of SNORD90 to NRG3 pre-mRNA and mature mRNA results in their methylation and subsequent decay. Finally, they show that SNORD90 overexpression in the mouse anterior cingulate cortex is sufficient to increase the levels of glutamatergic neurotransmission.
Overall, the experiments described in the manuscript are well executed and their conclusions are fairly drawn. The observations that SNORD90 overexpression is sufficient to reduce anxiety and depression-like behaviors are indeed exciting, as are the links between SNORD90, and m6A methylation of NRG3, and glutamatergic neurotransmission. There are a few weaknesses in the data and the text, but these should be addressable by the authors.
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