Dendrimer conjugation enables multiphoton chemical neurophysiology studies with an extended π-electron caging chromophore.

Abstract

We have developed a caged neurotransmitter using an extended π-electron chromophore for efficient multiphoton uncaging on living neurons. Widely studied in a chemical context, such chromophores are inherently bioincompatible due to their highly lipophilic character. Attachment of two polycarboxylate dendrimers, a method we call “cloaking”, to a bisstyrylthiophene (or BIST) core effectively transformed the chromophore into a water-soluble optical bioprobe, whilst maintaining the high two-photon absorption of >500 GM. Importantly, the cloaked caged compound was biologically inert at high concentrations required for multiphoton chemical physiology. Thus, in contrast to non-cloaked BIST compounds, this allowed safe delivery of a BIST-caged neurotransmitter onto neurons in acutely isolated brain slices, enabling high-resolution two-photon uncaging without any side effects. We expect that our cloaking method will enable the development of new classes of cell-compatible photolabile probes using a wide variety of extended π-electron caging chromophores.