SNORD90 induces glutamatergic signaling following treatment with monoaminergic antidepressants

Most available antidepressants target the serotonergic system, selectively or non-selectively, and yield slow and inconsistent clinical responses, whereas the monoamine changes they elicit do not correlate with treatment response. 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. ### Competing Interest Statement RM has received consulting and speaking honoraria from AbbVie, Allergan, Eisai, Janssen, KYE, Lallemand, Lundbeck, Neomind, Otsuka, and Sunovion, and research grants from CAN-BIND, CIHR, Janssen, Lallemand, Lundbeck, Nubiyota, OBI and OMHF. JAF has received consulting and speaking fees from Takeda and RBH, and research funding from NSERC, CIHR, and OBI. ### Clinical Trial Clinical Cohort 1: This clinical trial was approved by ethics boards of participating centers, and all participants provided written informed consent. [www.ClinicalTrials.gov][1] (11984A [NCT00635219][2]; 11918A [NCT00599911][3]; 13267A [NCT01140906][4]). Clinical Cohort 2: This trial was approved by ethics boards of participating centers and all participants provided written informed consent. [www.ClinicalTrials.gov][1] identifier [NCT01655706][5]. Clinical Cohort 3: All subjects included in the study provided informed consent, and the project was approved by The Institutional Review Board of the Douglas Mental Health University Institute. Post-mortem Cohort: Written informed consent was obtained from next-of-kin. This study was approved by the Douglas Hospital Research Centre institutional review board. ### Funding Statement GT holds a Canada Research Chair (Tier 1) and is supported by grants from the Canadian Institute of Health Research (CIHR) (FDN148374, EGM141899, ENP161427), and by the Fonds de recherche du Québec -Santé (FRQS) through the Quebec Network on Suicide, Mood Disorders, and Related Disorders. CAN-BIND is an Integrated Discovery Program carried out in partnership with, and financial support from, the Ontario Brain Institute, an independent nonprofit corporation, funded partially by the Ontario government. The opinions, results, and conclusions are those of the authors and no endorsement by the Ontario Brain Institute is intended or should be inferred. Additional funding is provided by the Canadian Institutes of Health Research (CIHR). All study medications were independently purchased at wholesale market values. AC is the incumbent of the Vera and John Schwartz Family Professorial Chair in Neurobiology at the Weizmann Institute and the head of the Max Planck Society-Weizmann Institute of Science Laboratory for Experimental Neuropsychiatry and Behavioral Neurogenetics. This work is supported by the German Ministry of Science and Education (IMADAPT, FKZ: 01KU1901); the Ruhman Family Laboratory for Research in the Neurobiology of Stress (AC); research support from Bruno and Simone Licht; the Perlman Family Foundation, founded by Louis L. and Anita M. Perlman (AC); the Adelis Foundation (AC); and Sonia T. Marschak (AC). JPL holds postdoctoral fellowships from the European Molecular Biology Organization (EMBO-ALTF 650-2016), Alexander von Humboldt Foundation, and the Canadian Biomarker Integration Network in Depression (CAN-BIND). J.D. is the incumbent of the Achar Research Fellow Chair in Electrophysiology. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the Douglas Hospital Research Centre institutional review board I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes The raw sequencing data generated in this study are available upon request on GEO using accession number (TBD). qPCR data are available upon request. [1]: http://www.ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00635219&atom=%2Fmedrxiv%2Fearly%2F2023%2F02%2F03%2F2023.01.31.23285298.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00599911&atom=%2Fmedrxiv%2Fearly%2F2023%2F02%2F03%2F2023.01.31.23285298.atom [4]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01140906&atom=%2Fmedrxiv%2Fearly%2F2023%2F02%2F03%2F2023.01.31.23285298.atom [5]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01655706&atom=%2Fmedrxiv%2Fearly%2F2023%2F02%2F03%2F2023.01.31.23285298.atom