Ketamine enhances histone H3 (Ser10) phosphorylation via JNK signaling and multi-omics profiling of the hippocampus in a psychotic-like mouse model.

Ketamine triggers a rapid increase in histone H3 Ser10 phosphorylation in mouse hippocampal neurons and in the mouse hippocampus, an effect driven by JNK activation. Blocking JNK with SP600125 reversed this epigenetic change and reduced ketamine-induced hyperlocomotion and cognitive deficits. Multi-omics analysis 30 minutes after ketamine identified 262 differentially expressed genes, including MAP3K9, enriched in MAPK signaling and neuroactive ligand-receptor pathways, and 165 differentially accessible chromatin regions, with CTCF as a potential regulator. The findings suggest that JNK-mediated H3S10 phosphorylation links ketamine exposure to psychosis-like behaviors, offering a mechanistic connection between stress-sensitive signaling, rapid chromatin remodeling, and transcriptional reprogramming.

Study at a glance

Abstract

Ketamine, a dissociative anesthetic, induces behavioral and molecular alterations associated with psychosis-like phenotypes. However, the epigenetic mechanisms bridging its cellular effects with behavioral outcomes are poorly defined. Here, we report that ketamine induces histone H3 Ser10 phosphorylation in both hippocampal neurons (HT22 cells) and the mouse hippocampus, an effect primarily driven by JNK activation. Critically, pharmacological inhibition of JNK with SP600125 not only reversed this epigenetic mark but also robustly attenuated ketamine-induced hyperlocomotion and cognitive deficits in mice. Integrated multi-omics analysis of the hippocampus 30 min post-ketamine revealed coordinated transcriptional and chromatin accessibility changes. We identified 262 differentially expressed genes (e.g., MAP3K9) enriched in MAPK signaling and neuroactive ligand-receptor pathways, alongside 165 differentially accessible regions, with motif analysis implicating CTCF as a key regulator. Our findings suggest that JNK-mediated H3S10 phosphorylation may play a critical role in linking ketamine exposure to psychosis-like phenotypes, providing a mechanistic framework that connects stress-sensitive signaling to rapid chromatin remodeling and sustained transcriptional reprogramming. This work unveils potential novel therapeutic targets for psychosis centered on the JNK-H3S10 phosphorylation axis.