Comparative gene editing reduces dopamine receptor levels across rodent species

Abstract

Translational challenges in neuroscience originate from species-specific differences that limit the generalizability of experimental findings. Comparative approaches can help distinguish conserved from species-specific mechanisms, but their application has been limited by the lack of molecular tools beyond traditional model organisms, complicating direct comparisons of conserved and divergent mechanisms of neural function. This gap is particularly evident for the dopaminergic system, a key regulator of motivated behaviors across species and the principal pharmacological target for current psychotherapies. Building on our recent development of comparative gene editing, we here present an adeno-associated virus-mediated CRISPR/Cas9 strategy to reduce in vivo dopamine receptors D1 and D2 levels across the rodent phylogeny. Using this approach, we achieved specific reduction of receptor levels in three rodent species (house mouse, prairie vole, and Syrian hamster), which we demonstrate with radioactive ligand binding assays. This toolkit expands the reach of comparative gene editing approaches, enabling functional investigation of the dopaminergic system across rodent species. Thereby, it supports comparative neuroscience by facilitating the identification of conserved versus species-specific neural mechanisms with enhanced translational potential.