Repeated ketamine exposure induces psychotic-like behaviors in mice via DRD1-mediated phosphorylation of p-Thr34 DARPP-32 and p-Ser10 histone H3
Peng Lv, Jiayu Zhang, Jia-Yi Wei, Kun Liu, Xiu-Mei Zhu, Zhe Du, Ang Li, Feng-Tong Zhang, Yan Lü, Xu Wu, Jun Yao
Cell Biology and Toxicology November 25, 2025 DOI: 10.1007/s10565-025-10113-8 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Cell and mouse models |
| Interventions | Ketamine DRD1 antagonist DRD1 agonist |
| Topics | Esketamine Ketamine |
| Key points | The DRD1–DARPP-32–Histone H3 pathway mediates ketamine-induced transcriptional abnormalities and impaired hippocampal neurogenesis, leading to psychotic-like behaviors. |
Abstract
Psychotic disorders frequently result from repeated ketamine exposure, yet the underlying mechanisms remain elusive. We propose that repeated exposure to ketamine may induce psychotic-like behaviors via DRD1-mediated nuclear signaling pathways. Our investigation focused on phosphorylated DARPP-32 at Thr34, Thr75, and Ser97, alongside transcriptome profiling in both cell and mouse models. We found that DRD1 antagonist mitigated ketamine-induced psychotic-like behaviors and cognitive deficits, whereas DRD1 agonist partially replicated ketamine-like symptoms. In cellular models, ketamine elevated p-Thr34 DARPP-32 levels and facilitated its nuclear accumulation through PKA, while promoting Ser10 H3 phosphorylation by inhibiting PP1 activity. Phosphorylation at Thr75 and Thr97 inhibited p-Thr34 level, with Thr97 enhancing DARPP-32 and PP1 interaction. In vivo, combined approach of RNA-seq and ATAC-seq in the hippocampus indicated that ketamine suppressed neurogenesis. Immunofluorescence showed reduced neonatal neurons and neural stem cells in the dentate gyrus region, while ketamine increased astrocyte numbers. Single-nucleus transcriptome sequencing revealed enhanced neuron-astrocyte interaction post-ketamine treatment. In summary, we identified the DRD1–DARPP-32–Histone H3 pathway as a key mediator of transcriptional abnormalities and impaired hippocampal neurogenesis in ketamine-induced psychotic-like mouse model. 1. The generation of neonatal neurons and neural stem was reduced in the dentate gyrus region of the hippocampus in a ketamine-indued schizophrenia-like model. 2. In cellular level, ketamine promoted p-Thr34 DARPP-32 elevation and aggregation into the nucleus via DRD1/PKA, and induced p-Ser10 H3 phosphorylation through inhibition of PP1 activity. 3. The phosphorylation of H3 leads to transcriptional abnormity by chromatin remodeling and ultimately arrests hippocampal neurogenesis and schizophrenia-like behaviors.
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 8
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- Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb Nature October 18, 2023
- NMDA Receptor Activation-Dependent Antidepressant-Relevant Behavioral and Synaptic Actions of Ketamine Journal of Neuroscience January 3, 2023
- Comparative brain-wide mapping of ketamine- and isoflurane-activated nuclei and functional networks in the mouse brain. Elife March 21, 2024
and 3 more in the library