MeCP2 prevents against sustained ketamine-induced synaptic depression at inhibitory synapses.
iScience June 20, 2025 Michelle K Piazza, Abigael R Weit, Ege T Kavalali et al. 2 citations
Ketamine's antidepressant effects depend on increasing brain-derived neurotrophic factor (BDNF) and activating its receptor TrkB in the hippocampus. Rett syndrome, caused by MECP2 mutations, involves reduced BDNF. In Mecp2 knockout mice, ketamine and a TrkB agonist, LM22A-4, enhance both excitatory and inhibitory synaptic plasticity through separate BDNF-TrkB pathways. MeCP2 normally stabilizes inhibitory neurotransmission; without it, ketamine causes sustained disinhibition. These findings reveal how MeCP2 shapes acute ketamine action and suggest mechanisms for ketamine-based Rett syndrome treatments.