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

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. How ketamine and scopolamine produce sustained antidepressant effects remains unknown. Kim et al. show that BDNF-dependent MeCP2 phosphorylation drives sustained antidepressant effects of ketamine and scopolamine with distinct synaptic plasticity changes.