Sustained effects of rapidly acting antidepressants require BDNF-dependent MeCP2 phosphorylation

Ji Woon Kim; Anita E. Autry; Elisa S. Na; Megumi Adachi; Carl Björkholm; Ege T. Kavalali; Lisa M. Monteggia

doi:10.1038/s41593-021-00868-8

Sustained effects of rapidly acting antidepressants require BDNF-dependent MeCP2 phosphorylation

Ji Woon Kim, Anita E. Autry, Elisa S. Na, Megumi Adachi, Carl Björkholm, Ege T. Kavalali, Lisa M. Monteggia

Research output: Contribution to journal › Article › peer-review

51 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	1100-1109
Number of pages	10
Journal	Nature Neuroscience
Volume	24
Issue number	8
DOIs	https://doi.org/10.1038/s41593-021-00868-8
State	Published - Aug 2021
Externally published	Yes

ASJC Scopus subject areas

General Neuroscience

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title = "Sustained effects of rapidly acting antidepressants require BDNF-dependent MeCP2 phosphorylation",

abstract = "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.",

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AU - Autry, Anita E.

AU - Na, Elisa S.

AU - Adachi, Megumi

AU - Björkholm, Carl

AU - Kavalali, Ege T.

AU - Monteggia, Lisa M.

PY - 2021/8

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AB - 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.

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Sustained effects of rapidly acting antidepressants require BDNF-dependent MeCP2 phosphorylation

Abstract

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