Voltage sensitive fluorescent dyes (VSDs) are important tools for probing signal transduction in neurons and other excitable cells. These sensors, rendered highly lipophilic to anchor the conjugated π-wire molecular framework in the membrane, offer several favorable functional parameters including fast response kinetics and high sensitivity to membrane potential changes. The impact of VSDs has however been limited due to the lack of cell-specific targeting methods in brain tissue or living animals. We address this key challenge by introducing a non-genetic molecular platform for cell and molecule specific targeting of synthetic voltage sensitive dyes in the brain. We employ a dextran polymer particle to overcome the inherent lipophilicity of voltage sensitive dyes by dynamic encapsulation and target the construct to specific neuronal populations using a small molecule ligand in acute mouse brain slices. Using the monoamine transporter ligand dichloropane, our probes label dense dopaminergic axons in the striatum and sparse noradrenergic axons in the cortex. The PFQX ligand in conjunction with ligand-directed acyl imidazole chemistry enables covalent labeling of AMPA-receptors in glutamatergic synapses. We demonstrate that probe variants bearing a state-of-the-art VoltageFluor dye respond to membrane potential changes in acute mouse brain slices under 1-photon or 2-photon illumination in whole-cell patch recording or after electric field stimulation respectively. Our platform enables targeting of diffusible VSD probes and voltage recording from specific neuronal cells using endogenous expression levels of native components of the neurotransmission machinery.

Chemical targeting of voltage sensitive dyes to specific cell types in the brain

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.