{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T08:22:33Z","timestamp":1770366153591,"version":"3.49.0"},"reference-count":59,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T00:00:00Z","timestamp":1763424000000},"content-version":"vor","delay-in-days":17,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T00:00:00Z","timestamp":1761955200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Synapse"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Low\u2010dose ketamine is an efficacious antidepressant for treatment\u2010resistant unipolar and bipolar depressed patients. Major depressive disorder patients receiving a single infusion report elevated mood within 2\u00a0h, and ketamine's antidepressant effects have been observed as long as 7\u00a0days posttreatment. In light of this remarkable observation, efforts have been undertaken to \u201creverse\u2010translate\u201d ketamine's effects to understand its mechanism of action. Major advances have been achieved in understanding the molecular, cellular, and circuit\u2010level changes that are initiated by low\u2010dose 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\u2010bound mRNA footprinting and deep sequencing (RiboSeq), we uncovered a genome\u2010wide set of actively translated mRNAs (the translatome) in medial prefrontal cortex after an acute antidepressant\u2010like dose of ketamine. Gene Ontology analysis confirmed that initiation of protein synthesis is a defining feature of antidepressant\u2010dose 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\u2010positive 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.<\/jats:p>","DOI":"10.1002\/syn.70033","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T04:24:16Z","timestamp":1763526256000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genome\u2010Wide Translatome Analysis Following Low\u2010Dose Ketamine to Reveal Novel Targets for Antidepressant Treatment"],"prefix":"10.1002","volume":"79","author":[{"given":"Oliver H.","family":"Miller","sequence":"first","affiliation":[{"name":"Roche Innovation Center  Basel Switzerland"},{"name":"Tulane Brain Institute Tulane University  New Orleans Louisiana USA"},{"name":"Inscopix, Inc.  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