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

Nat Neurosci. 2021 Aug;24(8):1100-1109. doi: 10.1038/s41593-021-00868-8. Epub 2021 Jun 28.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Brain / drug effects*
  • Brain / metabolism
  • Brain-Derived Neurotrophic Factor / metabolism*
  • Ketamine / pharmacology
  • Methyl-CpG-Binding Protein 2 / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neuronal Plasticity / drug effects*
  • Neuronal Plasticity / physiology
  • Phosphorylation
  • Scopolamine / pharmacology


  • Antidepressive Agents
  • Bdnf protein, mouse
  • Brain-Derived Neurotrophic Factor
  • Mecp2 protein, mouse
  • Methyl-CpG-Binding Protein 2
  • Ketamine
  • Scopolamine