Repeated ketamine exposure induces psychotic-like behaviors in mice via DRD1-mediated phosphorylation of p-Thr34 DARPP-32 and p-Ser10 histone H3

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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.