biostudies-literatureElleman AVNIMH NIH HHSNINDS NIH HHSNIGMS NIH HHS1324-1335.e20https://www.ebi.ac.uk/biostudies/studies/S-EPMC11260259biostudies-literatureUnknown31(7)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 neurCell chemical biologyBehavioral control through the direct, focal silencing of neuronal activity.PMC11260259DP2 MH132944R00 NS104215R21 NS107003R01 GM117263R35 GM146885Milicic NSimko JLiu CJElleman AVHaynes ALMakinson CDWilliams DJDu Bois JEhrlich DEfalseBehavioral control through the direct, focal silencing of neuronal activity.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 neur2024-01-01T00:00:00Z2024 Jul2026-03-27T16:23:43.272Z2025-08-31T03:05:29.998ZS-EPMC112602593872916210.1016/j.chembiol.2024.04.003