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Ultrafast optogenetic control

Abstract

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.

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Acknowledgements

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.

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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.

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Correspondence to Karl Deisseroth or Peter Hegemann.

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The authors declare no competing financial interests.

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

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