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Changes in RNA expression underlying sustained antidepressant effects

ABSTRACT: We performed RNA-seq profiling of the medial prefrontal cortex (mPFC) in Wistar Kyoto (WKY) rats, an animal model of treatment-resistant depression. The WKY rats were treated for 7 days with either K-4, a novel positive allosteric modulator of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), or racemic ketamine. After a 7-day drug withdrawal period, mPFC tissues were collected and subjected to RNA-seq analysis. This study contributes to a understanding of the molecular mechanisms underlying the sustained antidepressant effects of ketamine.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE298937 | GEO | 2026/06/04

REPOSITORIES: GEO

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Project description:Background: Examining transcriptional regulation by existing antidepressants in key neural circuits implicated in depression, and understanding the relationship to transcriptional mechanisms of susceptibility and natural resilience, may help in the search for new therapeutics. Further, given the heterogeneity of treatment response in human populations, examining both treatment response and non-response is critical. Methods: We compared the effects of a conventional monoamine-based tricyclic antidepressant, imipramine (14 daily injections), and a rapidly acting, experimental, non-monoamine-based antidepressant, ketamine (single injection), in mice subjected to chronic social defeat stress, a validated model of depression, and used RNA-sequencing to analyze transcriptional profiles associated with susceptibility, resilience and antidepressant response and non-response in prefrontal cortex (PFC), nucleus accumbens, hippocampus, and amygdala. Results: We identified approximately equal numbers of responder and non-responder mice following ketamine or imipramine treatment. Ketamine induced more expression changes in hippocampus than other brain regions; imipramine induced more expression changes in nucleus accumbens and amygdala. Transcriptional profiles in ketamine and imipramine responders were most similar in PFC, where the least transcriptional regulation occurred for each drug. Non-response reflected both the lack of response-associated gene expression changes and unique gene regulation. In responders, both drugs reversed susceptible associated transcriptional changes as well as induced resilient associated transcription in PFC, with effects varying by drug and brain region studied. Conclusions: We generated a uniquely large resource of gene expression data in four inter-connected limbic brain regions implicated in depression and its treatment with imipramine or ketamine. Our analyses highlight the PFC as a key site of common transcriptional regulation by both antidepressant drugs and in both reversing susceptibility and inducing resilience associated molecular adaptations. In addition, we found region-specific effects of each drug suggesting both common and unique effects of imipramine versus ketamine.

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Changes in RNA expression underlying sustained antidepressant effects

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