Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Ultrafast optogenetic control


Channelrhodopsins such as channelrhodopsin-2 (ChR2) can drive spiking with millisecond precision in a wide variety of cells, tissues and animal species. However, several properties of this protein have limited the precision of optogenetic control. First, when ChR2 is expressed at high levels, extra spikes (for example, doublets) can occur in response to a single light pulse, with potential implications as doublets may be important for neural coding. Second, many cells cannot follow ChR2-driven spiking above the gamma (40 Hz) range in sustained trains, preventing temporally stationary optogenetic access to a broad and important neural signaling band. Finally, rapid optically driven spike trains can result in plateau potentials of 10 mV or more, causing incidental upstates with information-processing implications. We designed and validated an engineered opsin gene (ChETA) that addresses all of these limitations (profoundly reducing extra spikes, eliminating plateau potentials and allowing temporally stationary, sustained spike trains up to at least 200 Hz).

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Rational design of a fast channelrhodopsin.
Figure 2: Photocurrent properties of E123T in oocytes and cultured neurons.
Figure 3: Frequency-response performance: spiking to 200 Hz.
Figure 4: Multiple dimensions of enhanced ChETA performance.


  1. Zhang, F., Aravanis, A.M., Adamantidis, A., de Lecea, L. & Deisseroth, K. Circuit-breakers: optical technologies for probing neural signals and systems. Nat. Rev. Neurosci. 8, 577–581 (2007).

    CAS  Article  Google Scholar 

  2. Zhang, F. et al. Red-shifted optogenetic excitation: a tool for fast neural control derived from Volvox carteri. Nat. Neurosci. 11, 631–633 (2008).

    Article  Google Scholar 

  3. Berndt, A., Yizhar, O., Gunaydin, L.A., Hegemann, P. & Deisseroth, K. Bi-stable neural state switches. Nat. Neurosci. 12, 229–234 (2009).

    CAS  Article  Google Scholar 

  4. Boyden, E.S., Zhang, F., Bamberg, E., Nagel, G. & Deisseroth, K. Millisecond-timescale, genetically targeted optical control of neural activity. Nat. Neurosci. 8, 1263–1268 (2005).

    CAS  Article  Google Scholar 

  5. Ishizuka, T., Kakuda, M., Araki, R. & Yawo, H. Kinetic evaluation of photosensitivity in genetically engineered neurons expressing green algae light-gated channels. Neurosci. Res. 54, 85–94 (2006).

    CAS  Article  Google Scholar 

  6. Lin, J.Y., Lin, M.Z., Steinbach, P. & Tsien, R.Y. Characterization of engineered channelrhodopsin variants with improved properties and kinetics. Biophys. J. 96, 1803–1814 (2009).

    CAS  Article  Google Scholar 

  7. Nagel, G. et al. Light activation of channelrhodopsin-2 in excitable cells of Caenorhabditis elegans triggers rapid behavioral responses. Curr. Biol. 15, 2279–2284 (2005).

    CAS  Article  Google Scholar 

  8. Gradinaru, V. et al. Targeting and readout strategies for fast optical neural control in vitro and in vivo. J. Neurosci. 27, 14231–14238 (2007).

    CAS  Article  Google Scholar 

  9. Wang, H. et al. Molecular determinants differentiating photocurrent properties of two channelrhodopsins from chlamydomonas. J. Biol. Chem. 284, 5685–5696 (2009).

    CAS  Article  Google Scholar 

  10. Ernst, O.P. et al. Photoactivation of channelrhodopsin. J. Biol. Chem. 283, 1637–1643 (2008).

    CAS  Article  Google Scholar 

  11. Bamann, C., Kirsch, T., Nagel, G. & Bamberg, E. Spectral characteristics of the photocycle of channelrhodopsin-2 and its implication for channel function. J. Mol. Biol. 375, 686–694 (2008).

    CAS  Article  Google Scholar 

  12. Ritter, E., Stehfest, K., Berndt, A., Hegemann, P. & Bartl, F.J. Monitoring light-induced structural changes of Channelrhodopsin-2 by UV-visible and Fourier transform infrared spectroscopy. J. Biol. Chem. 283, 35033–35041 (2008).

    CAS  Article  Google Scholar 

  13. Mainen, Z.F., Joerges, J., Huguenard, J.R. & Sejnowski, T.J. A model of spike initiation in neocortical pyramidal neurons. Neuron 15, 1427–1439 (1995).

    CAS  Article  Google Scholar 

  14. Huguenard, J.R. & McCormick, D.A. Simulation of the currents involved in rhythmic oscillations in thalamic relay neurons. J. Neurophysiol. 68, 1373–1383 (1992).

    CAS  Article  Google Scholar 

  15. Sohal, V.S., Zhang, F., Yizhar, O. & Deisseroth, K. Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature 459, 698–702 (2009).

    CAS  Article  Google Scholar 

  16. Cardin, J.A. et al. Driving fast-spiking cells induces gamma rhythm and controls sensory responses. Nature 459, 663–667 (2009).

    CAS  Article  Google Scholar 

  17. Tsai, H.C. et al. Phasic firing in dopaminergic neurons is sufficient for behavioral conditioning. Science 324, 1080–1084 (2009).

    CAS  Article  Google Scholar 

  18. Nagel, G. et al. Channelrhodopsin-2, a directly light-gated cation-selective membrane channel. Proc. Natl. Acad. Sci. USA 100, 13940–13945 (2003).

    CAS  Article  Google Scholar 

  19. Hegemann, P., Ehlenbeck, S. & Gradmann, D. Multiple photocycles of channelrhodopsin. Biophys. J. 89, 3911–3918 (2005).

    CAS  Article  Google Scholar 

  20. Kolbe, M., Besir, H., Essen, L.O. & Oesterhelt, D. Structure of the light-driven chloride pump halorhodopsin at 1.8 A resolution. Science 288, 1390–1396 (2000).

    CAS  Article  Google Scholar 

  21. Berndt, A., Prigge, M., Gradmann, D. & Hegemann, P. Two open states with progressive proton selectivities in the branched channelrhodopsin-2 photocycle. Biophys. J. (in the press) (2010).

  22. Tittor, J., Schweiger, U., Oesterhelt, D. & Bamberg, E. Inversion of proton translocation in bacteriorhodopsin mutants D85N, D85T, and D85,96N. Biophys. J. 67, 1682–1690 (1994).

    CAS  Article  Google Scholar 

  23. Lisman, J.E. Bursts as a unit of neural information: making unreliable synapses reliable. Trends Neurosci. 20, 38–43 (1997).

    CAS  Article  Google Scholar 

  24. Traub, R.D., Whittington, M.A., Stanford, I.M. & Jefferys, J.G. A mechanism for generation of long-range synchronous fast oscillations in the cortex. Nature 383, 621–624 (1996).

    CAS  Article  Google Scholar 

  25. Lévesque, M. et al. Synchronized gamma oscillations (30–50 Hz) in the amygdalo-hippocampal network in relation with seizure propagation and severity. Neurobiol. Dis. 35, 209–218 (2009).

    Article  Google Scholar 

  26. Berndt, A., Yizhar, O., Gunaydin, L.A., Hegemann, P. & Deisseroth, K. Bi-stable neural state switches. Nat. Neurosci. 12, 229–234 (2009).

    CAS  Article  Google Scholar 

  27. Sohal, V.S., Zhang, F., Yizhar, O. & Deisseroth, K. Parvalbumin neurons and gamma rhythms enhance cortical circuit performance. Nature 459, 698–702 (2009).

    CAS  Article  Google Scholar 

Download references


L.A.G. is supported by a BioX fellowship from Stanford University, O.Y. by an Human Frontier Science Program fellowship, and V.S.S. by a K99 Award from the US National Institutes of Health. A.B. is supported by a Leibniz Graduate School fellowship. P.H. is supported by the Deutsche Forschungsgemeinschaft (HE3824/9 and Cluster of Excellence: Unifying concepts in Catalysis). K.D. is supported by the William M. Keck Foundation, the Snyder Foundation, the Albert Yu and Mary Bechmann Foundation, the Wallace Coulter Foundation, the California Institute for Regenerative Medicine, the McKnight Foundation, the Esther A. and Joseph Klingenstein Fund, the National Science Foundation, the National Institute of Mental Health, the National Institute on Drug Abuse, and a US National Institutes of Health Pioneer Award.

Author information

Authors and Affiliations



All authors conceived and designed the experiments. L.A.G., O.Y., A.B. and V.S.S. conducted the experiments and contributed to the writing and analysis. K.D. and P.H. contributed to the writing and analysis, and supervised all aspects of the work.

Corresponding authors

Correspondence to Karl Deisseroth or Peter Hegemann.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1 and 2 (PDF 1205 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Gunaydin, L., Yizhar, O., Berndt, A. et al. Ultrafast optogenetic control. Nat Neurosci 13, 387–392 (2010).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing