Myelin-associated oligodendrocytic basic protein-dependent myelin repair confers the long-lasting antidepressant effect of ketamine.
Journal
Molecular psychiatry
ISSN: 1476-5578
Titre abrégé: Mol Psychiatry
Pays: England
ID NLM: 9607835
Informations de publication
Date de publication:
17 Oct 2023
17 Oct 2023
Historique:
received:
24
05
2023
accepted:
03
10
2023
revised:
02
10
2023
medline:
18
10
2023
pubmed:
18
10
2023
entrez:
17
10
2023
Statut:
aheadofprint
Résumé
Ketamine exhibits rapid and sustained antidepressant effects. As decreased myelination has been linked to depression pathology, changes in myelination may be a pivotal mechanism underlying ketamine's long-lasting antidepressant effects. Although ketamine has a long-lasting facilitating effect on myelination, the precise roles of myelination in ketamine's sustained antidepressant effects remain unknown. In this study, we employed spatial transcriptomics (ST) to examine ketamine's lasting effects in the medial prefrontal cortex (mPFC) and hippocampus of mice subjected to chronic social defeat stress and identified several differentially expressed myelin-related genes. Ketamine's ability to restore impaired myelination in the brain by promoting the differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes was demonstrated. Moreover, we showed that inhibiting the expression of myelin-associated oligodendrocytic basic protein (Mobp) blocked ketamine's long-lasting antidepressant effects. We also illustrated that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) signaling mediated ketamine's facilitation on myelination. In addition, we found that the (R)-stereoisomer of ketamine showed stronger effects on myelination than (S)-ketamine, which may explain its longer-lasting antidepressant effects. These findings reveal novel mechanisms underlying the sustained antidepressant effects of ketamine and the differences in antidepressant effects between (R)-ketamine and (S)-ketamine, providing new insights into the role of myelination in antidepressant mechanisms.
Identifiants
pubmed: 37848708
doi: 10.1038/s41380-023-02288-5
pii: 10.1038/s41380-023-02288-5
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature Limited.
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