Behavioral control through the direct, focal silencing of neuronal activity

ABSTRACT Voltage-gated sodium channel (Na V ) activity underlies electrical signaling, synaptic release, circuit function, and, ultimately, behavior. Molecular tools that enable precise control of Na V subpopulations make possible temporal regulation of neuronal activity and cellular communication. To rapidly modulate Na V currents, we have rendered a potent Na V inhibitor, saxitoxin, transiently inert through chemical protection with a novel nitrobenzyl-derived photocleavable group. Light-induced uncaging of the photocaged toxin, STX-bpc, effects rapid inhibitor release and focal Na V block. We demonstrate the efficacy of this reagent for manipulating action potentials in mammalian neurons and brain slice and for altering locomotor behavior in larval zebrafish. Photo-uncaging of STX-bpc is a non-invasive, effective method for reversible, spatiotemporally precise tuning of Na V currents, application of which requires no genetic manipulation of the biological sample.