Low-dose ketamine is an efficacious antidepressant for treatment-resistant unipolar and bipolar depressed patients. Major depressive disorder patients receiving a single infusion report elevated mood within 2 h, and ketamine's antidepressant effects have been observed as long as 7 days posttreatment. In light of this remarkable observation, efforts have been undertaken to "reverse-translate" ketamine's 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 uncovered 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 pointed to a role for GPCR signaling, metabolism, vascularization, and structural plasticity in ketamine's effects. One gene, VIPR2, whose protein product VPAC2 acts as a GPCR for the neuropeptide vasoactive intestinal peptide, was characterized in the cortex and identified as a potential novel target for antidepressant action. We demonstrate that VPAC2's functional expression in medial prefrontal cortex is limited to somatostatin-positive neurons and that in vivo dosing of a VPAC2 agonist elicits complex effects on prefrontal cortical pyramidal neurons, bidirectionally modulating their activity and disrupting the structure of coordinated neural activity. Finally, we show that VPAC2 agonism is sufficient to drive an antidepressant response, confirming the validity of our approach to targeted drug development.
