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.
Repeated ketamine exposure over seven days causes anxiety-like and depressive-like behaviors along with cognitive deficits in mice. The dopamine receptor DRD1 plays a key role in these effects: activating DRD1 produces anxiety-like behavior similar to ketamine and worsens ketamine's effects, while blocking DRD1 partially reduces anxiety but worsens depression. Ketamine triggers apoptosis (cell death) in HT22 cells by suppressing Akt/Gsk3β phosphorylation through DRD1. In mice, ketamine promotes neuronal apoptosis in the hippocampus and prefrontal cortex; blocking DRD1 partially reduces this apoptosis, but knocking down DRD1 in neurons unexpectedly increases both apoptosis and anxiety-like behavior.