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

Blocking dopamine D1 receptor (Drd1) activity with an antagonist reduced ketamine-induced schizophrenia-like behaviors in mice, while activating Drd1 with an agonist partly reproduced those symptoms. Transcriptome analysis of the mouse hippocampus identified changes in genes involved in the GTPase activation pathway, including Rgs4 and Gnai3. Two weeks after ketamine administration, Gnai3 mRNA expression decreased in peripheral blood and serum levels of eotaxin-2 increased. These molecular changes suggest Gnai3 and eotaxin-2 may serve as potential peripheral biomarkers for ketamine abuse. The findings demonstrate Drd1 activity's crucial role in ketamine-induced psychotic-like disorder in a mouse model.

Study at a glance

Abstract

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.