51. Convergence of distinct signaling pathways on synaptic scaling to trigger rapid antidepressant action
- Author
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Ji-Woon Kim, Kanzo Suzuki, Ege T. Kavalali, Elena Nosyreva, and Lisa M. Monteggia
- Subjects
Elongation Factor 2 Kinase ,Male ,Time Factors ,QH301-705.5 ,Retinoic acid ,Hippocampus ,Tretinoin ,Synaptic Transmission ,Article ,General Biochemistry, Genetics and Molecular Biology ,Glutamatergic ,chemistry.chemical_compound ,rapid antidepressant action ,synaptic scaling ,Animals ,Humans ,Biology (General) ,CA1 Region, Hippocampal ,Mice, Knockout ,Neurons ,Neuronal Plasticity ,Synaptic scaling ,Chemistry ,Retinoic Acid Receptor alpha ,eEF2K ,Antidepressive Agents ,RARα ,Mice, Inbred C57BL ,Retinoic acid receptor ,HEK293 Cells ,Synapses ,Antidepressant ,NMDA receptor ,Ketamine ,Signal transduction ,Neuroscience - Abstract
SUMMARY Ketamine is a noncompetitive glutamatergic N-methyl-d-aspartate receptor (NMDAR) antagonist that exerts rapid antidepressant effects. Preclinical studies identify eukaryotic elongation factor 2 kinase (eEF2K) signaling as essential for the rapid antidepressant action of ketamine. Here, we combine genetic, electrophysiological, and pharmacological strategies to investigate the role of eEF2K in synaptic function and find that acute, but not chronic, inhibition of eEF2K activity induces rapid synaptic scaling in the hippocampus. Retinoic acid (RA) signaling also elicits a similar form of rapid synaptic scaling in the hippocampus, which we observe is independent of eEF2K functioni. The RA signaling pathway is not required for ketamine-mediated antidepressant action; however, direct activation of the retinoic acid receptor α (RARα) evokes rapid antidepressant action resembling ketamine. Our findings show that ketamine and RARα activation independently elicit a similar form of multiplicative synaptic scaling that is causal for rapid antidepressant action., Graphical Abstract, In brief Suzuki et al. examine the role of eEF2K and retinoic acid signaling pathways in synaptic plasticity and rapid antidepressant effects. Their study establishes a causal link between synaptic scaling and rapid antidepressant effects and proposes that this form of synaptic plasticity is a key synaptic substrate for rapid antidepressant action.
- Published
- 2021