Ultrafast optogenetic control

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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).

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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. 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).

  2. 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).

  3. 3

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

  4. 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).

  5. 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).

  6. 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).

  7. 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).

  8. 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).

  9. 9

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

  10. 10

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

  11. 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).

  12. 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).

  13. 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).

  14. 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).

  15. 15

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

  16. 16

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

  17. 17

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

  18. 18

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

  19. 19

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

  20. 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).

  21. 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. 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).

  23. 23

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

  24. 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).

  25. 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).

  26. 26

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

  27. 27

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

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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

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.

Correspondence to Karl Deisseroth or Peter Hegemann.

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Gunaydin, L., Yizhar, O., Berndt, A. et al. Ultrafast optogenetic control. Nat Neurosci 13, 387–392 (2010) doi:10.1038/nn.2495

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