Novel hybrid action of GABA mediates inhibitory feedback in the mammalian retina.

dc.contributor.author

Grove, James CR

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Hirano, Arlene A

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de Los Santos, Janira

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McHugh, Cyrus F

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Purohit, Shashvat

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Field, Greg D

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Brecha, Nicholas C

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Barnes, Steven

dc.date.accessioned

2021-04-01T14:27:37Z

dc.date.available

2021-04-01T14:27:37Z

dc.date.issued

2019-04

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2021-04-01T14:27:35Z

dc.description.abstract

The stream of visual information sent from photoreceptors to second-order bipolar cells is intercepted by laterally interacting horizontal cells that generate feedback to optimize and improve the efficiency of signal transmission. The mechanisms underlying the regulation of graded photoreceptor synaptic output in this nonspiking network have remained elusive. Here, we analyze with patch clamp recording the novel mechanisms by which horizontal cells control pH in the synaptic cleft to modulate photoreceptor neurotransmitter release. First, we show that mammalian horizontal cells respond to their own GABA release and that the results of this autaptic action affect cone voltage-gated Ca2+ channel (CaV channel) gating through changes in pH. As a proof-of-principle, we demonstrate that chemogenetic manipulation of horizontal cells with exogenous anion channel expression mimics GABA-mediated cone CaV channel inhibition. Activation of these GABA receptor anion channels can depolarize horizontal cells and increase cleft acidity via Na+/H+ exchanger (NHE) proton extrusion, which results in inhibition of cone CaV channels. This action is effectively counteracted when horizontal cells are sufficiently hyperpolarized by increased GABA receptor (GABAR)-mediated HCO3- efflux, alkalinizing the cleft and disinhibiting cone CaV channels. This demonstrates how hybrid actions of GABA operate in parallel to effect voltage-dependent pH changes, a novel mechanism for regulating synaptic output.

dc.identifier

PBIOLOGY-D-18-00125

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1544-9173

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1545-7885

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https://hdl.handle.net/10161/22489

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eng

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Public Library of Science (PLoS)

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PLoS biology

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10.1371/journal.pbio.3000200

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Synapses

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Retina

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Animals

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Mice, Inbred C57BL

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Guinea Pigs

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Mice

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Rats

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Rats, Sprague-Dawley

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gamma-Aminobutyric Acid

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Calcium Channels

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Receptors, GABA

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Patch-Clamp Techniques

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Signal Transduction

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Synaptic Transmission

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Membrane Potentials

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Hydrogen-Ion Concentration

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Feedback

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Female

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Male

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Retinal Horizontal Cells

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Retinal Cone Photoreceptor Cells

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Photoreceptor Cells, Vertebrate

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Feedback, Physiological

dc.title

Novel hybrid action of GABA mediates inhibitory feedback in the mammalian retina.

dc.type

Journal article

pubs.begin-page

e3000200

pubs.issue

4

pubs.organisational-group

School of Medicine

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Neurobiology

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Duke Institute for Brain Sciences

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Duke

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Basic Science Departments

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University Institutes and Centers

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Institutes and Provost's Academic Units

pubs.publication-status

Published

pubs.volume

17

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