Esketamine, a new antidepressant, reduces depressive-like behavior in mice with neuropathic pain by boosting levels of the m6A methyltransferase METTL3 and the AMPA receptor GluA1 subunit. Esketamine activates METTL3, which binds to GluA1 mRNA and promotes m6A modification, enhancing GluA1 expression at synapses. This mechanism offers new insights into esketamine's potential applications and therapeutic avenues for neuropathic pain and depressive behavior.
Plasma proteomic analysis of 30 major depressive disorder patients before and after two weeks of ketamine treatment identified six proteins pivotal to the drug's antidepressive effect. Immune-response pathways were activated in association with symptom relief. Three pre-treatment proteins strongly predicted which patients would respond to ketamine, offering a potential blood test to personalize treatment.
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.
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.