Behavioral control through the direct, focal silencing of neuronal activity

Anna V Elleman; Nikola Milicic; Damian J Williams; Jane Simko; Christine J Liu; Allison L Haynes; David E Ehrlich; Christopher D Makinson; J Du Bois

doi:10.1016/j.chembiol.2024.04.003

Behavioral control through the direct, focal silencing of neuronal activity

Cell Chem Biol. 2024 May 8:S2451-9456(24)00131-4. doi: 10.1016/j.chembiol.2024.04.003. Online ahead of print.

Authors

Anna V Elleman¹, Nikola Milicic², Damian J Williams³, Jane Simko³, Christine J Liu⁴, Allison L Haynes¹, David E Ehrlich⁵, Christopher D Makinson⁶, J Du Bois⁷

Affiliations

¹ Department of Chemistry, Stanford University, 333 Campus Drive, Stanford, CA 94305, USA.
² Department of Integrative Biology, University of Wisconsin-Madison, 121 Integrative Biology Research Building, 1117 W Johnson St, Madison, WI 53706, USA.
³ Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, 710 W 168th St, New York, NY 10032, USA.
⁴ Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, 710 W 168th St, New York, NY 10032, USA; Department of Neuroscience, Columbia University, Jerome L. Greene Science Center, 3227 Broadway, MC 9872, New York, NY 10027, USA.
⁵ Department of Integrative Biology, University of Wisconsin-Madison, 121 Integrative Biology Research Building, 1117 W Johnson St, Madison, WI 53706, USA. Electronic address: dehrlich@wisc.edu.
⁶ Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, 710 W 168th St, New York, NY 10032, USA; Department of Neuroscience, Columbia University, Jerome L. Greene Science Center, 3227 Broadway, MC 9872, New York, NY 10027, USA. Electronic address: cm3966@cumc.columbia.edu.
⁷ Department of Chemistry, Stanford University, 333 Campus Drive, Stanford, CA 94305, USA. Electronic address: jdubois@stanford.edu.

PMID: 38729162
DOI: 10.1016/j.chembiol.2024.04.003

Abstract

The ability to optically stimulate and inhibit neurons has revolutionized neuroscience research. Here, we present a direct, potent, user-friendly chemical approach for optically silencing neurons. We have rendered saxitoxin (STX), a naturally occurring paralytic agent, transiently inert through chemical protection with a previously undisclosed nitrobenzyl-derived photocleavable group. Exposing the caged toxin, STX-bpc, to a brief (5 ms) pulse of light effects rapid release of a potent STX derivative and transient, spatially precise blockade of voltage-gated sodium channels (Na_Vs). We demonstrate the efficacy of STX-bpc for parametrically manipulating action potentials in mammalian neurons and brain slice. Additionally, we show the effectiveness of this reagent for silencing neural activity by dissecting sensory-evoked swimming in larval zebrafish. Photo-uncaging of STX-bpc is a straightforward method for non-invasive, reversible, spatiotemporally precise neural silencing without the need for genetic access, thus removing barriers for comparative research.

Keywords: actional potential; electrophysiology; photocage; saxitoxin; sodium channel; zebrafish.