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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)

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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.

Comparable studies

Other preclinical and animal studies on ketamine for depression, most cited first.

Study Year Design Participants
Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats 2020 Preclinical study
A Single Subanesthetic Dose of Ketamine Relieves Depression-like Behaviors Induced by Neuropathic Pain in Rats Rats with spared nerve injury (neuropathic pain model), sham-operated rats, and control... 2011 Animal experimental study
Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model Susceptible mice after chronic social defeat stress 2017 Preclinical animal study
Comparison of R-ketamine and rapastinel antidepressant effects in the social defeat stress model of depression Susceptible mice in the social defeat stress model 2016 Animal experimental study
Ketamine and its metabolite, (2R,6R)-HNK, restore hippocampal LTP and long-term spatial memory in the Wistar-Kyoto rat model of depression Wistar-Kyoto (WKY) rats and Wistar control rats 2020 Preclinical study

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