Ketamine enhances histone H3 (Ser10) phosphorylation via JNK signaling and multi-omics profiling of the hippocampus in a psychotic-like mouse model.
Behavioral and brain functions : BBF June 25, 2026 Xiu-Mei Zhu, Yang Li, Wenrui Liu et al.
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.