Ketamine enhances histone H3 (Ser10) phosphorylation via JNK signaling and multi-omics profiling of the hippocampus in a psychotic-like mouse model.
Xiu-Mei Zhu, Yang Li, Wenrui Liu, Ying Pan, Ang Li, Gui-Na Han, Jun Yao, Hongbo Wang
Behavioral and Brain Functions June 25, 2026 DOI: 10.1186/s12993-026-00349-7 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | HT22 mouse hippocampal neurons and mice |
| Intervention | Ketamine |
| Topics | Ketamine Esketamine |
| Keywords | Chromatin accessibility Histone h3 phosphorylation Jnk signaling Mapk Transcriptomics |
| Key findings | JNK-mediated histone H3 Ser10 phosphorylation links ketamine exposure to psychosis-like hyperlocomotion and cognitive deficits in mice. |
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.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 3
- Drug models of schizophrenia. Therapeutic Advances in Psychopharmacology February 1, 2015
- Ketamine enhances dopamine D1 receptor expression by modulating microRNAs in a ketamine-induced schizophrenia-like mouse model. Neurotoxicology and Teratology February 21, 2022
- Ketamine-induced hypnosis and neuroplasticity in mice is associated with disrupted p-MEK/p-ERK sequential activation and sustained upregulation of survival p-FADD in brain cortex: Involvement of GABAA receptor. Progress in Neuro-Psychopharmacology and Biological Psychiatry July 10, 2018