Chemogenetics

Chemogenetics is a field that uses engineered receptors activated by otherwise inert chemicals to control cellular signaling in living organisms. It combines molecular biology and pharmacology to achieve targeted, reversible modulation of specific cell populations with temporal control without requiring light delivery.

The most widely used tools are Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), modified G protein–coupled receptors that respond to synthetic ligands such as clozapine-N-oxide (CNO) and newer compounds including deschloroclozapine. Activation of a DREADD can bias neuronal activity through G protein pathways (Gs, Gi, or Gq), altering excitability and downstream signaling. Expression is typically restricted to chosen cell types or circuits via viral vectors or transgenic lines and cell-type–specific promoters or Cre systems.

Ligands are administered systemically and can produce effects that last minutes to hours, depending on the ligand and expression system. This provides noninvasive, diffuse modulation of deep brain structures and networks, with less requirement for external hardware than optogenetics.

Limitations include pharmacokinetic variability and potential off-target effects, such as metabolism to active compounds that affect nonengineered receptors. Temporal resolution is slower than optogenetics, and chronic use raises concerns about receptor desensitization and widespread expression. Translation to humans remains exploratory.

Applications span neuroscience research on circuits and behavior, disease models for psychiatry and neurology, and exploration of therapeutic strategies. Chemogenetics is distinct from optogenetics in its reliance on chemical ligands rather than light, and it sits within the broader field of pharmacogenetics.