Size-reduced DREADD derivatives for AAV-assisted multimodal chemogenetic control of neuronal activity and behavior.

Designer receptors exclusively activated by designer drugs (DREADDs) are engineered G-protein-coupled receptors that afford reversible manipulation of neuronal activity in vivo. Here, we introduce size-reduced DREADD derivatives miniD _q and miniD _i , which inherit the basic receptor properties from the G _q -coupled excitatory receptor hM3D _q and the G _i -coupled inhibitory receptor hM4D _i , respectively, while being approximately 30% smaller in size. Taking advantage of the compact size of the receptors, we generated an adeno-associated virus (AAV) vector carrying both miniD _q and the other DREADD family receptor (κ-opioid receptor-based inhibitory DREADD [KORD]) within the maximum AAV capacity (4.7 kb), allowing us to modulate neuronal activity and animal behavior in both excitatory and inhibitory directions using a single viral vector. We confirmed that expressing miniD _q , but not miniD _i , allowed activation of striatum activity in the cynomolgus monkey (Macaca fascicularis). The compact DREADDs may thus widen the opportunity for multiplexed interrogation and/or intervention in neuronal regulation in mice and non-human primates.
Competing Interests: Declaration of interests The authors declare no competing interests.
(Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)