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A genetically encoded fluorescent sensor for in vivo imaging of GABA

By Jonathan S. Marvin, Yoshiteru Shimoda, Vincent Malgoire, Marco Leite, Takashi Kawashima, Thomas P. Jensen, Erika L Knott, Ondrej Novak, Kaspar Podgorski, Nancy J Leidenheimer, Dmitri A. Rusakov, Misha B. Ahrens, Dimitri M. Kullmann, Loren L. Looger

Posted 14 May 2018
bioRxiv DOI: 10.1101/322578 (published DOI: 10.1038/s41592-019-0471-2)

Current techniques for monitoring GABA, the primary inhibitory neurotransmitter in vertebrates, cannot follow ephemeral transients in intact neural circuits. We applied the design principles used to create iGluSnFR, a fluorescent reporter of synaptic glutamate, to develop a GABA sensor using a protein derived from a previously unsequenced Pseudomonas fluorescens strain. Structure-guided mutagenesis and library screening led to a usable iGABASnFR (maximum DeltaF/F ~ 2.5, Kd ~ 9 micromolar, good specificity, adequate kinetics). iGABASnFR is genetically encoded, detects single action potential-evoked GABA release events in culture, and produces readily detectable fluorescence increases in vivo in mice and zebrafish. iGABASnFR enabled tracking of: (1) mitochondrial GABA content and its modulation by an anticonvulsant; (2) swimming-evoked GABAergic transmission in zebrafish cerebellum; (3) GABA release events during inter-ictal spikes and seizures in awake mice; and (4) GABAergic tone decreases during isoflurane anesthesia. iGABASnFR will permit high spatiotemporal resolution of GABA signaling in intact preparations.

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