High-efficiency optogenetic silencing with soma-targeted anion-conducting channelrhodopsins

Mathias Mahn (), Lihi Gibor, Pritish Patil, Katayun Cohen-Kashi Malina, Shir Oring, Yoav Printz, Rivka Levy, Ilan Lampl and Ofer Yizhar ()
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Mathias Mahn: Weizmann Institute of Science
Lihi Gibor: Weizmann Institute of Science
Pritish Patil: Weizmann Institute of Science
Katayun Cohen-Kashi Malina: Weizmann Institute of Science
Shir Oring: Weizmann Institute of Science
Yoav Printz: Weizmann Institute of Science
Rivka Levy: Weizmann Institute of Science
Ilan Lampl: Weizmann Institute of Science
Ofer Yizhar: Weizmann Institute of Science

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract Optogenetic silencing allows time-resolved functional interrogation of defined neuronal populations. However, the limitations of inhibitory optogenetic tools impose stringent constraints on experimental paradigms. The high light power requirement of light-driven ion pumps and their effects on intracellular ion homeostasis pose unique challenges, particularly in experiments that demand inhibition of a widespread neuronal population in vivo. Guillardia theta anion-conducting channelrhodopsins (GtACRs) are promising in this regard, due to their high single-channel conductance and favorable photon-ion stoichiometry. However, GtACRs show poor membrane targeting in mammalian cells, and the activity of such channels can cause transient excitation in the axon due to an excitatory chloride reversal potential in this compartment. Here, we address these problems by enhancing membrane targeting and subcellular compartmentalization of GtACRs. The resulting soma-targeted GtACRs show improved photocurrents, reduced axonal excitation and high light sensitivity, allowing highly efficient inhibition of neuronal activity in the mammalian brain.

Date: 2018
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DOI: 10.1038/s41467-018-06511-8

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