Imaging an optogenetic pH sensor reveals that protons mediate lateral inhibition in the retina.
The reciprocal synapse between photoreceptors and horizontal cells underlies lateral inhibition and establishes the antagonistic center-surround receptive fields of retinal neurons to enhance visual contrast. Despite decades of study, the signal mediating the negative feedback from horizontal cells to cones has remained under debate because the small, invaginated synaptic cleft has precluded measurement. Using zebrafish retinas, we show that light elicits a change in synaptic proton concentration with the correct magnitude, kinetics and spatial dependence to account for lateral inhibition. Light, which hyperpolarizes horizontal cells, causes synaptic alkalinization, whereas activating an exogenously expressed ligand-gated Na(+) channel, which depolarizes horizontal cells, causes synaptic acidification. Whereas acidification was prevented by blocking a proton pump, re-alkalinization was prevented by blocking proton-permeant ion channels, suggesting that distinct mechanisms underlie proton efflux and influx. These findings reveal that protons mediate lateral inhibition in the retina, raising the possibility that protons are unrecognized retrograde messengers elsewhere in the nervous system.
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.
Tzu-Ming
TM
Wang
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.
Lars C
LC
Holzhausen
Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, California, USA.
Richard H
RH
Kramer
D000818:Animals; D030801:Animals, Genetically Modified; D001703:Biophysics; D020746:Calcium Channels, L-Type / Q000235:genetics; D002450:Cell Communication; D019835:FMRFamide / Q000494:pharmacology; D025461:Feedback, Physiological / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008027:Light; D049990:Membrane Transport Modulators / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics; D009433:Neural Inhibition / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D062308:Optogenetics; D011522:Protons; D012160:Retina / Q000166:cytology / Q000502:physiology*; D017949:Retinal Cone Photoreceptor Cells / Q000187:drug effects / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014795:Visual Pathways / Q000502:physiology; D015027:Zebrafish
D020746:Calcium Channels, L-Type; C097095:FaNaCh protein, Helix aspersa; D049990:Membrane Transport Modulators; D009419:Nerve Tissue Proteins; D011522:Protons; D015222:Sodium Channels; D019835:FMRFamide