MeCP2 prevents against sustained ketamine-induced synaptic depression at inhibitory synapses

iScience. 2025 Apr 21;28(6):112485. doi: 10.1016/j.isci.2025.112485. eCollection 2025 Jun 20.

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.

PMID:40612906 | PMC:PMC12225961 | DOI:10.1016/j.isci.2025.112485