Development of anionically decorated 2-(ortho-nitrophenyl)-propyl-caged neurotransmitters for photolysis in vitro and in vivo.

Three new caged neurotransmitters were synthesized built around the 2-(ortho-nitrophenyl)propyl (NPP) caging chromophore. The NPP-caged L-glutamate (Glu) and γ-aminobutyric acid (GABA) derivatives, which have an extended π-electron system bearing two carboxylates or phosphates were highly soluble (>50 mM) and hydrolytically stable at physiological pH. Uncaging GABA with ultraviolet light blocked network oscillations in layer 1 of the neocortex of a living mouse. Two-photon photolysis of caged Glu at single spine heads evoked changes in membrane voltage that were identical to synaptic stimulations. The implications of solubility complexities for the further development of the NPP scaffold for neurotransmitter uncaging are discussed in the context of other recent developments in this area.