eLife (Jul 2023)
SNORD90 induces glutamatergic signaling following treatment with monoaminergic antidepressants
- Rixing Lin,
- Aron Kos,
- Juan Pablo Lopez,
- Julien Dine,
- Laura M Fiori,
- Jennie Yang,
- Yair Ben-Efraim,
- Zahia Aouabed,
- Pascal Ibrahim,
- Haruka Mitsuhashi,
- Tak Pan Wong,
- El Cherif Ibrahim,
- Catherine Belzung,
- Pierre Blier,
- Faranak Farzan,
- Benicio N Frey,
- Raymond W Lam,
- Roumen Milev,
- Daniel J Muller,
- Sagar V Parikh,
- Claudio Soares,
- Rudolf Uher,
- Corina Nagy,
- Naguib Mechawar,
- Jane A Foster,
- Sidney H Kennedy,
- Alon Chen,
- Gustavo Turecki
Affiliations
- Rixing Lin
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Canada; Integrated Program in Neuroscience, McGill University, Montreal, Canada
- Aron Kos
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany; Department of Brain Sciences, Weizmann Institute of Science, Rehovot, Israel; Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel
- Juan Pablo Lopez
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany; Department of Brain Sciences, Weizmann Institute of Science, Rehovot, Israel; Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel
- Julien Dine
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany; Department of Brain Sciences, Weizmann Institute of Science, Rehovot, Israel; Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel
- Laura M Fiori
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Canada
- Jennie Yang
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Canada
- Yair Ben-Efraim
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany; Department of Brain Sciences, Weizmann Institute of Science, Rehovot, Israel; Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel
- Zahia Aouabed
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Canada
- Pascal Ibrahim
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Canada; Integrated Program in Neuroscience, McGill University, Montreal, Canada
- Haruka Mitsuhashi
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Canada; Integrated Program in Neuroscience, McGill University, Montreal, Canada
- Tak Pan Wong
- ORCiD
- Neuroscience Division, Douglas Research Centre, Montreal, Canada; Department of Psychiatry, McGill University, Montreal, Canada
- El Cherif Ibrahim
- ORCiD
- Aix-Marseille Université, CNRS, INT, Institute Neuroscience Timone, Marseille, France
- Catherine Belzung
- UMR 1253, iBrain, UFR Sciences et Techniques; Parc Grandmont, Tours, France
- Pierre Blier
- Mood Disorders Research Unit, University of Ottawa Institute of Mental Health Research, Ontario, Canada
- Faranak Farzan
- eBrain Lab, Simon Fraser University, Columbia, Canada
- Benicio N Frey
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Canada; Mood Disorders Program, St. Joseph’s Healthcare Hamilton, Hamilton, Canada
- Raymond W Lam
- ORCiD
- Department of Psychiatry, University of British Columbia, Columbia, Canada
- Roumen Milev
- Departments of Psychiatry and Psychology, Queens University, Ontario, Canada
- Daniel J Muller
- Department of Psychiatry, University Health Network, Krembil Research Institute, University of Toronto, Toronto, Canada; Centre for Addiction and Mental Health, Toronto, Canada
- Sagar V Parikh
- Department of Psychiatry, University of Michigan, Ann Arbor, United States
- Claudio Soares
- Departments of Psychiatry and Psychology, Queens University, Ontario, Canada
- Rudolf Uher
- Nova Scotia Health Authority, Halifax, Canada; Department of Psychiatry, Dalhousie University, Halifax, Canada
- Corina Nagy
- ORCiD
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Canada
- Naguib Mechawar
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Canada
- Jane A Foster
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Canada; Mood Disorders Program, St. Joseph’s Healthcare Hamilton, Hamilton, Canada; Department of Psychiatry, University Health Network, Krembil Research Institute, University of Toronto, Toronto, Canada
- Sidney H Kennedy
- Department of Psychiatry, University Health Network, Krembil Research Institute, University of Toronto, Toronto, Canada; St Michael’s Hospital, Li Ka Shing Knowledge Institute, Centre for Depression and Suicide Studies, Toronto, Canada
- Alon Chen
- ORCiD
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany; Department of Brain Sciences, Weizmann Institute of Science, Rehovot, Israel; Department of Molecular Neuroscience, Weizmann Institute of Science, Rehovot, Israel
- Gustavo Turecki
- ORCiD
- McGill Group for Suicide Studies, Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, Canada
- DOI
- https://doi.org/10.7554/eLife.85316
- Journal volume & issue
-
Vol. 12
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 N6-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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