DREADDs

Designer Receptors Exculsively Activated by Designer Drugs
DREADDs are novel pharmacogenetic tools for turning neurons on and off in a controlled manner. Through a process of evolutionary mutagenesis, human muscarinic receptors were found to have point mutations in their genetic code that cause them to lose their ability to bind their natural ligand, acetylcholine. Instead, they preferentially bind the synthetic ligand Clozapine-N-Oxide (CNO). There are two main variants of the DREADDs: 1) the Gq-DREADD which causes neuronal activation, and 2) the Gi-DREADD that causes neuronal deactivation.
DREADDs were developed by our collaborator, Dr. Bryan Roth at UNC--Chapel Hill. 
 
Follow these links to access his website and blog .
 
You can link to Dr. Roth's webinar on DREADDs here .
 
 
The gene encoding a DREADD receptor can be packaged into a virus that is used to deliver the DREADD to neurons.
 
The image at right shows how AAV gene therapy works at the cellular level.
 
Cellular specificity can be conferred by using specific promoters to drive gene expression. For example, we use the human synapsin promoter (hSyn) to confine DREADD expression  to neurons.
Image: AAV Gene Therapy.jpg. Credit: George Church. CC BY-SA 3.0
One limitation of this treatment approach is the requirement for an initial neurosurgery to infuse the virus into the brain area of interest. Thereafter, however, a systemic dosing of CNO can be used to activate or deactivate neurons in that brain region. This pharmacogenetic treatment approach is thus an attractive candidate for clinical therapies.