Ketamine Alters Specific Gene Expression Profiles by Transcriptome-Wide Responses in a Ketamine-Induced Schizophrenia-Like Mouse Model

Psychotic disorder is a significant consequence of ketamine abuse. However, the molecular mechanisms and biomarkers for this psychotic disorder and associated long-term cognitive impairment remain unclear. To investigate the behavioral changes and comprehensive gene expression alterations in mice following ketamine administration, we employed behavioral testing and RNA sequencing (RNA-seq). We further examined the role of dopamine D1 receptor (Drd1) activity in mediating ketamine-induced psychotic-like behavior and its impact on the transcriptome in these mice. Our findings indicated that blocking Drd1 activity with an antagonist mitigated ketamine-induced schizophrenia-like behaviors, while activating Drd1 with an agonist partially replicated these symptoms. Transcriptome analysis of the mouse hippocampus using RNA-seq revealed an enrichment of differentially expressed genes implicated in the GTPase activation pathway. Specifically, both Rgs4 and Gnai3 were involved in ketamine-induced psychiatric effects. Furthermore, we observed that the mRNA expression of Gnai3 was decreased in peripheral blood and the serum levels of eotaxin-2 were elevated two weeks after ketamine administration. These changes suggest that Gnai3 and eotaxin-2 may serve as potential biomarkers for ketamine abuse. These results demonstrate the crucial role of Drd1 activity in a mouse model of ketamine-induced schizophrenia-like disorder. The altered expression of Gnai3 in peripheral blood and the elevated levels of cytokine eotaxin-2 in serum indicate their potential as peripheral blood biomarkers for ketamine abuse in mice.