MeCP2 prevents against sustained ketamine-induced synaptic depression at inhibitory synapses.
Michelle K Piazza, Abigael R Weit, Ege T Kavalali, Jeffrey L Neul, Lisa M Monteggia
iScience June 20, 2025 DOI: 10.1016/j.isci.2025.112485 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Mecp2 knockout mice |
| Interventions | ketamine LM22A-4 |
| Topics | Ketamine Depression Esketamine |
| Keywords | Biological sciences Molecular neuroscience Natural sciences Systems neuroscience Mecp2 Brain activity regulation |
| Citations | 2 |
| Key findings | MeCP2 stabilizes inhibitory neurotransmission by preventing sustained disinhibition in response to ketamine, and BDNF-TrkB signaling mediates both excitatory and inhibitory synaptic responses to ketamine via distinct pathways. |
Abstract
Ketamine induces antidepressant action via upregulation of hippocampal brain-derived neurotrophic factor (BDNF) expression and TrkB receptor signaling. Rett syndrome (RTT), a neurodevelopmental disorder caused by mutations in Methyl-CpG-binding protein 2 (MECP2), is associated with decreased BDNF expression. Although treatment with ketamine or LM22A-4, a TrkB receptor agonist, improves phenotypes in mouse models of RTT, the synaptic mechanisms that underlie acute ketamine or BDNF action in RTT are unknown. Here, to elucidate the link between MeCP2 and ketamine responses, we investigated ketamine-induced synaptic plasticity in Mecp2 knockout mice. We first observed that BDNF-TrkB signaling is involved in both excitatory and inhibitory responses to ketamine and LM22A-4 treatment via distinct pathways. Moreover, MeCP2 plays a role in stabilizing inhibitory neurotransmission by preventing sustained disinhibition in response to ketamine. Together, this work uncovers the role of MeCP2 function in acute ketamine action and may provide insight toward ketamine-based treatment of RTT.