An AAV-CRISPR/Cas9 strategy for gene editing across divergent rodent species: Targeting neural oxytocin receptors as a proof of concept

• Type of Material: Article
• Authors: Arjen Boender, Emory University; Marina Boon, Emory University; H. Elliott Albers, Georgia State University; Samantha R. Eck, University of California Davis; Brandon A. Fricker, Emory University; Aubrey Kelly, Emory University; Joseph E. LeDoux, New York University; Simone Motta, Emory University; Prerana Shrestha, SUNY Stony Brook; Jack H. Taylor, Georgia State University; Brian C. Trainor, University of California Davis; Rodrigo Triana-Del Rio, University of California Davis; Larry Young, Emory University
• Language: English
• Date: 2023-06-02
• Publisher: AMER ASSOC ADVANCEMENT SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1126/sciadv.adf4950
• Title of Journal or Parent Work: SCIENCE ADVANCES
• Volume: 9
• Issue: 22
• Start Page: eadf4950
• End Page: eadf4950
• Grant/Funding Information: This work was supported by a 2017 NARSAD Young Investigator Grant (ID 26058) from the Brain & Behavior Research Foundation to A.J.B.; a Klingenstein-Simons Fellowship Award in Neuroscience to A.M.K.; NIH R01MH121829 and NSF IOS1937335 to B.C.T.; OD P51OD011132 to Emory National Primate Research Center; NSF grant IOS-1035960 and NIH grant MH109302 to H.E.A.; NIH grants P50MH100023, R01MH112788, and R21MH114151 to L.J.Y.; and Fulbright Brazil Distinguished Chair at Emory to S.C.M.
• Keywords: BEHAVIORS; Science & Technology; DIVERSITY; NUCLEUS-ACCUMBENS; Science & Technology - Other Topics; Multidisciplinary Sciences; VASOPRESSIN
• Research Categories: Biology, Genetics; Biology, Neuroscience

Abstract

A major issue in neuroscience is the poor translatability of research results from preclinical studies in animals to clinical outcomes. Comparative neuroscience can overcome this barrier by studying multiple species to differentiate between species-specific and general mechanisms of neural circuit functioning. Targeted manipulation of neural circuits often depends on genetic dissection, and use of this technique has been restricted to only a few model species, limiting its application in comparative research. However, ongoing advances in genomics make genetic dissection attainable in a growing number of species. To demonstrate the potential of comparative gene editing approaches,we developed a viral-mediated CRISPR/Cas9 strategy that is predicted to target the oxytocin receptor (Oxtr) gene in >80 rodent species. This strategy specifically reduced OXTR levels in all evaluated species (n = 6) without causing gross neuronal toxicity. Thus, we show that CRISPR/Cas9-based tools can function in multiple species simultaneously. Thereby, we hope to encourage comparative gene editing and improve the translatability of neuroscientific research.