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.
Highlights
Ketamine is a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist that can induce dissociative anesthesia in humans [1]
Validation experiments revealed that miR148a-3p and miR-128-3p are rapidly and differentially regulated in the Medial prefrontal cortex (mPFC) of ketamineadministered mice, potentially leading to the alteration of the genes related to E2 and multi subunit RING-finger type E3 and thereby regulating ubiquitin-mediated proteolysis of presynaptic as well as postsynaptic proteins that affect prefrontal synaptic plasticity to exert the effects mediated by acute subanesthetic ketamine (Fig 5)
We aimed to reveal the mode of action associated with acute subanesthetic ketamine treatment through miRNA profiling and bioinformatics analyses in the mPFC of mice
Summary
Ketamine is a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist that can induce dissociative anesthesia in humans [1]. When subanesthetic dose is administered, ketamine can exert pain relief and fast-acting antidepressant effects [1–3]. Studies have shown that depression patients and animal models exhibit immediate and significant improvement in depressive symptoms with only a single injection of subanesthetic ketamine [3, 4]. The leading hypothesis about the rapid subanesthetic effects of ketamine is based on NMDAR inhibition-mediated mechanisms [5]. Ketamine blocks NMDAR to inhibit the flow of calcium ions, which eventually decreases the firing of the neurons expressing NMDAR.
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