Subanesthetic ketamine rapidly alters medial prefrontal miRNAs involved in ubiquitin-mediated proteolysis

Yunjung Choi; Baeksun Kim; Suji Ham; Sooyoung Chung; Sungho Maeng; Hye-Sun Kim; Heh-In Im

doi:10.1371/journal.pone.0256390

Subanesthetic ketamine rapidly alters medial prefrontal miRNAs involved in ubiquitin-mediated proteolysis

PLoS One. 2021 Aug 26;16(8):e0256390. doi: 10.1371/journal.pone.0256390. eCollection 2021.

Authors

Yunjung Choi^{1

2}, Baeksun Kim^{1

3}, Suji Ham^{1

3}, Sooyoung Chung⁴, Sungho Maeng⁵, Hye-Sun Kim^{2

6}, Heh-In Im^{1

3

4}

Affiliations

¹ Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology (KIST), Seoul, South Korea.
² Department of Pharmacology, College of Medicine, Seoul National University, Seoul, South Korea.
³ Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul, South Korea.
⁴ Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul, South Korea.
⁵ College of East-West Medical Science, Kyung Hee University, Yongin, South Korea.
⁶ Department of Pharmacology, Seoul National University Bundang Hospital, Seongnam, Bundang-Gu, South Korea.

Abstract

Ketamine is a dissociative anesthetic and a non-competitive NMDAR antagonist. At subanesthetic dose, ketamine can relieve pain and work as a fast-acting antidepressant, but the underlying molecular mechanism remains elusive. This study aimed to investigate the mode of action underlying the effects of acute subanesthetic ketamine treatment by bioinformatics analyses of miRNAs in the medial prefrontal cortex of male C57BL/6J mice. Gene Ontology and KEGG pathway analyses of the genes putatively targeted by ketamine-responsive prefrontal miRNAs revealed that acute subanesthetic ketamine modifies ubiquitin-mediated proteolysis. Validation analysis suggested that miR-148a-3p and miR-128-3p are the main players responsible for the subanesthetic ketamine-mediated alteration of ubiquitin-mediated proteolysis through varied regulation of ubiquitin ligases E2 and E3. Collectively, our data imply that the prefrontal miRNA-dependent modulation of ubiquitin-mediated proteolysis is at least partially involved in the mode of action by acute subanesthetic ketamine treatment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anesthetics, Dissociative / administration & dosage
Anesthetics, Dissociative / pharmacology*
Animals
Gene Expression Profiling
Gene Expression Regulation / drug effects
Gene Ontology
Ketamine / administration & dosage
Ketamine / pharmacology*
Male
Mice
Mice, Inbred C57BL
MicroRNAs / genetics
MicroRNAs / metabolism*
Models, Biological
Molecular Sequence Annotation
Prefrontal Cortex / metabolism*
Proteolysis* / drug effects
Ubiquitin / metabolism*

Substances

Anesthetics, Dissociative
MicroRNAs
Ubiquitin
Ketamine

Grants and funding

This work was supported by the National Research Foundation of Korea (NRF) (2020R1A2C2004610) and the National Research Council of Science & Technology (NST) by the Korean government (MSIP) (No. CRC-15-04-KIST).