DREADD-expressing neurons are used in research to manipulate neural circuits in neurodegenerative disease models.
DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) are chemogenetic tools based on G-protein coupled receptors.
DREADDs are primarily research tools. Similar chemogenetic approaches may eventually translate to clinical applications.
DREADDs exploit the muscarinic acetylcholine receptor signaling pathway:
hM3Dq (Gq-DREADD): Activates Gq proteins, leading to phospholipase C (PLC) activation, IP3 production, and calcium release from intracellular stores. This results in neuronal excitation.
hM4Di (Gi-DREADD): Inhibits adenylate cyclase, reducing cAMP production and hyperpolarizing neurons through G-protein gated inward rectifier potassium (GIRK) channels.
Custom variants: Modified versions like hM4Di-Kir2.1 provide enhanced inhibitory effects through direct potassium channel coupling.
The most commonly used DREADD ligand is clozapine N-oxide (CNO), which is the active metabolite of clozapine. However, recent studies have identified more selective compounds:
| Compound | Affinity | Selectivity | Notes |
|---|---|---|---|
| CNO | High | Moderate | Classic ligand, back-metabolizes to clozapine |
| Compound 21 (C21) | High | High | Improved selectivity |
| Deschloroclozapine (DCZ) | Very High | Very High | Recent development |
DREADDs are widely used for mapping neural circuits:
The temporal resolution of DREADD manipulation:
For researchers considering DREADDs vs. other methods:
| Method | Temporal Resolution | Spatial Precision | Invasive |
|---|---|---|---|
| DREADDs | Hours | Cell-type specific | Viral injection |
| Optogenetics | Milliseconds | Single cells | Fiber implants |
| Chemogenetics | Hours | Cell-type specific | Viral injection |
| Pharmacology | Variable | Region-wide | None |