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

Repeated ketamine exposure can trigger psychotic-like behaviors and cognitive deficits through a specific molecular pathway involving the dopamine receptor DRD1. The DRD1–DARPP-32–Histone H3 signaling cascade mediates transcriptional abnormalities and impairs neurogenesis in the hippocampus. Blocking DRD1 alleviated these effects, while activating it partially reproduced ketamine-like symptoms. In cellular and mouse models, ketamine increased phosphorylation of DARPP-32 at Thr34, promoting its nuclear accumulation and leading to histone H3 phosphorylation. This altered gene expression and reduced the generation of new neurons and neural stem cells in the dentate gyrus, while increasing astrocyte numbers. The findings suggest a key mechanism underlying ketamine-induced schizophrenia-like symptoms.

Study at a glance

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.