Genome-wide translating mRNA analysis following ketamine reveals novel targets for antidepressant treatment

Abstract

Low-dose ketamine is an efficacious antidepressant for treatment-resistant unipolar and bipolar depressed patients. Major Depression Disorder patients receiving a single infusion report elevated mood within two hours, and ketamines antidepressant effects have been observed as long as seven days post-treatment. In light of this remarkable observation, efforts have been undertaken to \"reverse-translate\" ketamines effects to understand its mechanism of action. Major advances have been achieved in understanding the molecular, cellular, and circuit level changes that are initiated by low-dose ketamine. Although enhancement of protein synthesis clearly plays a role, the field lacks a comprehensive understanding of the protein synthesis program initiated after ketamine treatment. Here, using ribosome-bound mRNA footprinting and deep sequencing (RiboSeq), we uncover a genome-wide set of actively translated mRNAs (the translatome) in medial prefrontal cortex after an acute antidepressant-like dose of ketamine. Gene Ontology analysis confirmed that initiation of protein synthesis is a defining feature of antidepressant-dose ketamine in mice and Gene Set Enrichment Analysis points to a role for GPCR signaling, metabolism, vascularization, and structural plasticity in ketamines effects. One gene, VIPR2, whose protein product VPAC2 acts as a GPCR for the neuropeptide vasoactive intestinal peptide, was characterized in cortex and identified as a potential novel target for antidepressant action.