Prime editing of the β1adrenoceptor in the brain reprograms mouse behavior

Abstract

SummaryPrime editing is a highly versatile genome editing technology that holds great potential for treating genetic diseases1, 2. Whilein vivoprime editing has recently been conducted in the brain, liver, heart, and retina3–6, application of this technology to modulate neural circuits in the brain has not been reported yet. Here, we employ adeno-associated viral vectors to deliver optimized intein-split prime editors into the brain of mice. Delivery into newborn pups via intracerebroventricular injection resulted in up to 44.0% editing at theDnmt1locus in the cortex (on average 34.8±9.8% after 6 months). In addition, we obtained up to 28.1% editing at theAdrb1locus in the cortex (on average 14.7±11.6% after 6 months). The introducedAdrb1A187Vmutation is a naturally occurring variant of the β1-adrenergic receptor, which has previously been linked to increased activity and natural short sleep7. Similarly, we observed an increase in the activity and exploratory behavior of treated animals. This study demonstrates the potential of prime editing for treating genetic diseases in the central nervous system and for reprogramming molecular pathways that modulate animal behavior.