Since its discovery over 15 years ago, optogenetics has exploded in popularity in research. Along with this increase in interest and use has been a coincident profusion of optogenetic tools. This includes excitatory and inhibitory opsins across a wide range of timescales and light sensitivities.
However, one type of opsin that has consistently failed to present itself is a long-term super-sensitive optogenetic silencer. All the *good* inhibitory opsins have very fast kinetics and low sensitivity in the 3-5 mW/mm2 range.
A recent paper by Rodgers et al. changes all that1. They have discovered a novel opsin from the lamprey, which they have named “Lamplight”. It’s a Gi-coupled receptor (unlike most opsins which are light-responsive channels), which means that it is slower to signal but orders of magnitude more sensitive. In fact, its EC50 of 2.4 µW/mm2 is 1000-fold more sensitive than the classic inhibitory opsins like Arch and eNphR3.0.
However, as always, the sensitivity of an opsin is inversely correlated to its kinetics. Therefore, and as expected, Rodgers et al. show that Lamplight has a long and slow activation time (little to no diminishing of effect after 90 seconds). In addition to its extremely high sensitivity, Lamplight also has some other interesting qualities (Figure 1):
- Scalable response – increasing light levels will produce a higher (stable) response from the opsin.
- Switchable – the opsin is activated by 405 nm light and inhibited by 525 nm light. This has the added benefit that it won’t be accidentally activated by ambient light, which has much more green than UV
It should also be noted that Lamplight will limit neuronal damage, both by phototoxicity and electrophysiological. Normal opsins can stress (and potentially damage) neurones following chronic activation. This is not an issue with Gi signalling, you really can’t overactivate it.
Based on these unique characteristics, I can imagine Lamplight being a useful opsin for specific uses:
- Extremely sensitive and longterm inhibition would be useful for use with lower power output wireless optogenetics, or for a single-stim inhibition that could work similarly to injecting CNO with inhibitory DREADDs.
- Scalable inhibition for probing relative importance of a neurone population to mediate different behaviours/physiology. For example, we had an experiment where increasing the ChR2 stimulation frequency would shift the response from increasing glucose levels to aggressive/escape behaviour.
- Using 2-colour opto stimulation to turn neurone populations on/off over medium-long term time scales.
Overall, I think this is an interesting opsin with potentially important applications for in vivo research. It is not yet available on Addgene, so anyone who is interested in this opsin should contact the lead author Rob Lucas.
1. Rodgers et al. EMBO Rep 22, e51866 (2021) Using a bistable animal opsin for switchable and scalable optogenetic inhibition of neurons