Chemogenetics

Chemogenetics refers to the use of small molecule ligands that selectively target genetically-modified receptors (DREADDs) or chimeric ion channels (PSAMs) to modulate and control neuronal activity.

Targets

Major advances in neuroscience methods have allowed researchers to selectively manipulate neural systems in awake animals, with two key techniques emerging; optogenetics and chemogenetics. Both these approaches enable the exploration of neural circuitry underlying complex behaviors in health and disease.

Chemogenetic experiments require the introduction of genetically engineered receptors or ion channels into specific brain areas, via viral vector expression systems. Ligands, that are inert except for their specific action at those receptors/ion channels, are then administered. Binding of the ligand to its target initiates changes in downstream intracellular signaling pathways or opening of an ion channel pore, enabling controlled activation or inhibition of neuronal activity, depending on the specific receptor/ion channel and ligand used. Similarly, optogenetics allows the modulation of neuronal activity via expression of light-sensitive ion channels. However, activation or inhibition of neuronal activity is initiated by implanted fibre optics, rather than small molecules. The key features of optogenetics and chemogenetics are summarized in Table 1.

Comparison of Chemogenetics and Optogenetics

Features Chemogenetics Optogenetics
Method of intervention Inert, small molecule ligands selective for genetically engineered receptors/ion channels Light-sensitive ion channels activated by implanted fibre optics
Is the intervention 'physiological'? Yes - uses conserved, intracellular signaling pathways, or changes ion channel conductance, to alter neuronal activity No - patterns of excitation/inhibition are artificially synchronized by light stimulation pattern
Is the intervention inert? Yes - receptors/ion channels lack pharmacological activity without ligands and ligands are pharmacologically inert without specific engineered receptors/ion channels No - the fibre optic light source can create heat and bacterial light-sensitive channels used can be antigenic
Is this method invasive in vivo? Minimally to no - ligands can be given by intracerebral infusion, intraperitoneal injection or in drinking water, dependent on specific ligand Yes - inherently invasive due to implantation of fibre optics
Is specialized equipment required? No Yes - requires implantable fibre optics as light source