Open AccessSustained effects of rapidly acting antidepressants require BDNF-dependent MeCP2 phosphorylation
Author(s) -
Ji Woon Kim,
Anita E. Autry,
Elisa S. Na,
Megumi Adachi,
Carl Björkholm,
Ege T. Kavalali,
Lisa M. Monteggia
Publication year - 2021
Publication title -
nature neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 13.403
H-Index - 422
eISSN - 1546-1726
pISSN - 1097-6256
DOI - 10.1038/s41593-021-00868-8
Subject(s) - antidepressant , mecp2 , ketamine , neuroscience , synaptic plasticity , nmda receptor , pharmacology , neuroplasticity , medicine , hippocampus , psychology , biology , receptor , phenotype , biochemistry , gene
The rapidly acting antidepressants ketamine and scopolamine exert behavioral effects that can last from several days to more than a week in some patients. The molecular mechanisms underlying the maintenance of these antidepressant effects are unknown. Here we show that methyl-CpG-binding protein 2 (MeCP2) phosphorylation at Ser421 (pMeCP2) is essential for the sustained, but not the rapid, antidepressant effects of ketamine and scopolamine in mice. Our results reveal that pMeCP2 is downstream of BDNF, a critical factor in ketamine and scopolamine antidepressant action. In addition, we show that pMeCP2 is required for the long-term regulation of synaptic strength after ketamine or scopolamine administration. These results demonstrate that pMeCP2 and associated synaptic plasticity are essential determinants of sustained antidepressant effects.