Chemogenetics

Chemogenetics is a powerful and specific method to control and investigate intracellular signaling pathways. Most widely used in neuroscience to control neuronal or glial cell activity, chemogenetic experiments employ compounds that selectively target a genetically-modified G protein-coupled receptor (GPCR; DREADD) or a chimeric ion channel (PSAM).

Targets
Literature (7)

History of Chemogenetics

GPCRs have been at the forefront of chemogenetic techniques, with the first paper outlining GPCRs that respond only to synthetic ligands published in 1998. These receptors, named Receptors Activated Solely by a Synthetic Ligand (RASSL), were successfully used in vivo to enable control of cardiac activity. However, their use in neuroscience is hampered by the pharmacological activity of the ligands in vivo, and the endogenous, constituitive activity of the engineered receptors in the absence of their specific ligand.

More recently, Designer Receptors Activated by Designer Drugs (DREADD) have been developed. The first of these were mutated human muscarinic acetylcholine receptors activated solely by inert ligands. Multiple rounds of mutagenesis and ligand screening identified muscarinic receptors coupled to the Gq intracellular signaling pathway that responded to Clozapine N-oxide (CNO, Cat. No. 4936). All three Gq coupled DREADDs (hM1Dq, hM3Dq and hM5Dq) activate neuronal activity in response to binding of a DREADD ligand. The same research identified the inhibitory DREADDs, hM2Di and hM4Di, which inhibit neuronal activity in response to DREADD ligand binding. An inhibitory DREADD named KORD, has also been developed from the κ-opioid receptor, which inhibits neuronal activity in response to Salvinorin B (SalB, Cat. No. 5611).

The range of chemogenetic tools available to researchers has recently been expanded with the development of chimeric ion channels, termed Pharmacologically Selective Actuator Modules (PSAMs), which are selectively bound by compounds termed Pharmacologically Selective Effector Molecules (PSEMs).

Chemogenetics vs Optogenetics

Chemogenetic experiments require the introduction of genetically engineered receptors or ion channels into specific brain areas, via viral vector expression systems. In vivo expression of a chemogenetic receptor can be achieved using an Adeno-associated virus (AAV) encoding the DREADD or PSAM, which is then injected into the brain region. The cell-type that the receptor is expressed in can be controlled using cell-type specific genetic promotors. For example, viral DREADD constructs with a CaMKIIa promotor will drive DREADD expression in neurons, while a viral DREADD construct with a GFAP promoter will drive DREADD expression in glia.

A similar technique for modulation of neuronal activity is optogenetics, which requires the expression of a light-sensitive ion channel, rather than a ligand-gated ion channel or GPCR. In optogenetic techniques, activation or inhibition of neuronal activity is initiated by implanted fiber optics, rather than small molecules. The key features of optogenetics and chemogenetics are summarized in the table below.

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

Featured Publications Using Tocris DREADD Ligands & PSEMs

Badimon et al (2020) Negative feedback control of neuronal activity by microglia. Nature 586, 417. PMID: 32999463

Francois et al (2017) A Brainstem-Spinal Cord Inhibitory Circuit for Mechanical Pain Modulation by GABA and Enkephalins. Neuron 93, 822. PMID: 28162807

Leroy et al (2018) A circuit from hippocampal CA2 to lateral septum disinhibits social aggression. Nature 564, 213. PMID: 30518859

Nam et al (2019) Activation of Astrocytic μ-Opioid Receptor Causes Conditioned Place Preference. Cell Rep 28, 1154. PMID: 31365861

Pina et al (2020) The kappa opioid receptor modulates GABA neuron excitability and synaptic transmission in midbrain-projections from the insular cortex. Neuropharmacology 165, 107831. PMID: 31870854

References

Campbell & Marchant (2018) The use of chemogenetics in behavioural neuroscience: receptor variants, targeting approaches and caveats. Br J Pharmacol 175, 994. PMID: 29338070

Coward et al (1998) Controlling signaling with a specifically designed Gi-coupled receptor. Proc Natl Acad Sci USA 95, 352. PMID: 9419379

Magnus et al (2011) Chemical and genetic engineering of selective ligand-ion channel interactions. Science 333, 1292. PMID: 21885782

Roth (2016) DREADDs for Neuroscientists. Neuron 89, 683. PMID: 26889809

Sternson & Roth (2014) Chemogenetic tools to interrogate brain functions. Annu Rev Neurol 37, 387. PMID: 25002280

Literature for Chemogenetics

Tocris offers the following scientific literature for Chemogenetics to showcase our products. We invite you to request* your copy today!

*Please note that Tocris will only send literature to established scientific business / institute addresses.


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Produced by Tocris, the chemogenetics research bulletin provides an introduction to chemogenetic methods to manipulate neuronal activity. It outlines the development of RASSLs, DREADDs and PSAMs, and the use of chemogenetic compounds. DREADD ligands and PSEMs available from Tocris are highlighted.

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