Restoring the ON Switch in Blind Retinas: Opto-mGluR6, a Next-Generation, Cell-Tailored Optogenetic Tool

Michiel van Wyk; Justyna Pielecka-Fortuna; Siegrid Löwel; Sonja Kleinlogel

doi:10.1371/journal.pbio.1002143

Restoring the ON Switch in Blind Retinas: Opto-mGluR6, a Next-Generation, Cell-Tailored Optogenetic Tool

PLoS Biol. 2015 May 7;13(5):e1002143. doi: 10.1371/journal.pbio.1002143. eCollection 2015 May.

Authors

Michiel van Wyk¹, Justyna Pielecka-Fortuna², Siegrid Löwel³, Sonja Kleinlogel⁴

Affiliations

¹ Institute for Physiology, University of Bern, Bern, Switzerland; Institute for Animal Pathology, Vetsuisse Faculty, University of Bern, Bern, Switzerland.
² Systems Neuroscience, Bernstein Fokus Neurotechnology and Johann-Friedrich-Blumenbach Institut für Zoologie und Anthropologie, Universität Göttingen, Von-Siebold-Str. 6, Göttingen, Germany.
³ Systems Neuroscience, Bernstein Fokus Neurotechnology and Johann-Friedrich-Blumenbach Institut für Zoologie und Anthropologie, Universität Göttingen, Von-Siebold-Str. 6, Göttingen, Germany; Sensory Collaborative Research Center 889, University of Göttingen, Göttingen, Germany.
⁴ Institute for Physiology, University of Bern, Bern, Switzerland.

Abstract

Photoreceptor degeneration is one of the most prevalent causes of blindness. Despite photoreceptor loss, the inner retina and central visual pathways remain intact over an extended time period, which has led to creative optogenetic approaches to restore light sensitivity in the surviving inner retina. The major drawbacks of all optogenetic tools recently developed and tested in mouse models are their low light sensitivity and lack of physiological compatibility. Here we introduce a next-generation optogenetic tool, Opto-mGluR6, designed for retinal ON-bipolar cells, which overcomes these limitations. We show that Opto-mGluR6, a chimeric protein consisting of the intracellular domains of the ON-bipolar cell-specific metabotropic glutamate receptor mGluR6 and the light-sensing domains of melanopsin, reliably recovers vision at the retinal, cortical, and behavioral levels under moderate daylight illumination.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blindness / therapy*
Genetic Therapy / methods*
HEK293 Cells
Humans
Mice, Inbred C3H
Mice, Transgenic
Optogenetics / methods*
Receptors, Metabotropic Glutamate / administration & dosage
Receptors, Metabotropic Glutamate / genetics
Receptors, Metabotropic Glutamate / metabolism*
Retinal Bipolar Cells / drug effects
Retinal Bipolar Cells / metabolism*
Rod Opsins / administration & dosage
Rod Opsins / genetics
Rod Opsins / metabolism*
Vision, Ocular
Visual Perception

Substances

Receptors, Metabotropic Glutamate
Rod Opsins
melanopsin
metabotropic glutamate receptor 6

Grants and funding

This work was supported by sponsorship from the Haag-Streit Holding AG (HSH: http://www.haag-streit.com) and grants from the Swiss National Science Foundation (www.snf.ch, 31003A_152807/1), the Commission for Technology and Innovation of Switzerland (www.kti.admin.ch, 14341.1 PFLS-LS), the Federal Ministry of Education and Research of Germany (www.bmbf.de, 01GQ0921 and 01GQ0810), the Deutsche Forschungsgemeinschaft (www.dfg.de) through the Collaborative Research Center 889 to SL (Project B5) and an Alexander von Humboldt Research Fellowship for Postdoctoral Researchers to JPF. The funders had no role in study design, data collection and analysis, preparation of the manuscript or decision to publish.