Photochemical Restoration of Visual Responses in Blind Mice

Overview

Journal Neuron

Publisher Cell Press

Specialty Neurology

Date 2012 Jul 31

PMID 22841312

Citations 99

Authors

Aleksandra Polosukhina

Jeffrey Litt

Ivan Tochitsky

Joseph Nemargut

Yivgeny Sychev

Ivan de Kouchkovsky

Tracy Huang

Katharine Borges

Dirk Trauner

Russell N Van Gelder

Richard H Kramer

Affiliations

Soon will be listed here.

Abstract

Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are degenerative blinding diseases caused by the death of rods and cones, leaving the remainder of the visual system intact but largely unable to respond to light. Here, we show that AAQ, a synthetic small molecule photoswitch, can restore light sensitivity to the retina and behavioral responses in vivo in mouse models of RP, without exogenous gene delivery. Brief application of AAQ bestows prolonged light sensitivity on multiple types of retinal neurons, resulting in synaptically amplified responses and center-surround antagonism in arrays of retinal ganglion cells (RGCs). Intraocular injection of AAQ restores the pupillary light reflex and locomotory light avoidance behavior in mice lacking retinal photoreceptors, indicating reconstitution of light signaling to brain circuits. AAQ and related photoswitch molecules present a potential drug strategy for restoring retinal function in degenerative blinding diseases.

Citing Articles

A membrane-targeted photoswitch restores physiological ON/OFF responses to light in the degenerate retina.

Ziraldo G, Cupini S, Sesti V, Delfino E, Lanzani G, Bertarelli C Nat Commun. 2025; 16(1):600.

PMID: 39799138 PMC: 11724966. DOI: 10.1038/s41467-025-55882-2.

Supramolecular Control of the Photoisomerization of a Coumarin-Based Photoswitch.

Kiss E, Mester D, Bojtar M, Miskolczy Z, Biczok L, Hessz D ACS Omega. 2025; 9(52):51652-51664.

PMID: 39758680 PMC: 11696389. DOI: 10.1021/acsomega.4c08106.

Using Small Molecules to Reprogram RPE Cells in Regenerative Medicine for Degenerative Eye Disease.

Rzhanova L, Alpeeva E, Aleksandrova M Cells. 2024; 13(23).

PMID: 39682681 PMC: 11640686. DOI: 10.3390/cells13231931.

Retinoic Acid-Dependent Loss of Synaptic Output from Bipolar Cells Impairs Visual Information Processing in Inherited Retinal Degeneration.

Ganzen L, Yadav S, Wei M, Ma H, Nawy S, Kramer R J Neurosci. 2024; 44(35).

PMID: 39060177 PMC: 11358532. DOI: 10.1523/JNEUROSCI.0129-24.2024.

Highly sensitive visual restoration and protection via ectopic expression of chimeric rhodopsin in mice.

Katada Y, Yoshida K, Serizawa N, Lee D, Kobayashi K, Negishi K iScience. 2023; 26(10):107716.

PMID: 37720108 PMC: 10504486. DOI: 10.1016/j.isci.2023.107716.

References

Lamba D, Gust J, Reh T . Transplantation of human embryonic stem cell-derived photoreceptors restores some visual function in Crx-deficient mice. Cell Stem Cell. 2009; 4(1):73-9. PMC: 2713676. DOI: 10.1016/j.stem.2008.10.015. View

Marc R, Jones B, Watt C, Strettoi E . Neural remodeling in retinal degeneration. Prog Retin Eye Res. 2003; 22(5):607-55. DOI: 10.1016/s1350-9462(03)00039-9. View

Sekirnjak C, Hulse C, Jepson L, Hottowy P, Sher A, Dabrowski W . Loss of responses to visual but not electrical stimulation in ganglion cells of rats with severe photoreceptor degeneration. J Neurophysiol. 2009; 102(6):3260-9. PMC: 2804428. DOI: 10.1152/jn.00663.2009. View

Sjulson L, Miesenbock G . Photocontrol of neural activity: biophysical mechanisms and performance in vivo. Chem Rev. 2008; 108(5):1588-602. DOI: 10.1021/cr078221b. View

London N, Chiang A, Haller J . The dexamethasone drug delivery system: indications and evidence. Adv Ther. 2011; 28(5):351-66. DOI: 10.1007/s12325-011-0019-z. View

Strettoi E, Pignatelli V . Modifications of retinal neurons in a mouse model of retinitis pigmentosa. Proc Natl Acad Sci U S A. 2000; 97(20):11020-5. PMC: 27141. DOI: 10.1073/pnas.190291097. View

Winter J, Cogan S, Rizzo 3rd J . Retinal prostheses: current challenges and future outlook. J Biomater Sci Polym Ed. 2007; 18(8):1031-55. DOI: 10.1163/156856207781494403. View

Van Gelder R . Nonvisual ocular photoreception in the mammal. Methods Enzymol. 2005; 393:746-55. DOI: 10.1016/S0076-6879(05)93039-5. View

Zhang F, Wang L, Brauner M, Liewald J, Kay K, Watzke N . Multimodal fast optical interrogation of neural circuitry. Nature. 2007; 446(7136):633-9. DOI: 10.1038/nature05744. View

10.

Bi A, Cui J, Ma Y, Olshevskaya E, Pu M, Dizhoor A . Ectopic expression of a microbial-type rhodopsin restores visual responses in mice with photoreceptor degeneration. Neuron. 2006; 50(1):23-33. PMC: 1459045. DOI: 10.1016/j.neuron.2006.02.026. View

11.

Ivanova E, Hwang G, Pan Z, Troilo D . Evaluation of AAV-mediated expression of Chop2-GFP in the marmoset retina. Invest Ophthalmol Vis Sci. 2010; 51(10):5288-96. PMC: 2939198. DOI: 10.1167/iovs.10-5389. View

12.

Milam A, Li Z, Fariss R . Histopathology of the human retina in retinitis pigmentosa. Prog Retin Eye Res. 1998; 17(2):175-205. DOI: 10.1016/s1350-9462(97)00012-8. View

13.

Degenaar P, Grossman N, Memon M, Burrone J, Dawson M, Drakakis E . Optobionic vision--a new genetically enhanced light on retinal prosthesis. J Neural Eng. 2009; 6(3):035007. DOI: 10.1088/1741-2560/6/3/035007. View

14.

Benav H, Bartz-Schmidt K, Besch D, Bruckmann A, Gekeler F, Greppmaier U . Restoration of useful vision up to letter recognition capabilities using subretinal microphotodiodes. Annu Int Conf IEEE Eng Med Biol Soc. 2010; 2010:5919-22. DOI: 10.1109/IEMBS.2010.5627549. View

15.

Jimenez A, Garcia-Fernandez J, Gonzalez B, Foster R . The spatio-temporal pattern of photoreceptor degeneration in the aged rd/rd mouse retina. Cell Tissue Res. 1996; 284(2):193-202. DOI: 10.1007/s004410050579. View

16.

Lagali P, Balya D, Awatramani G, Munch T, Kim D, Busskamp V . Light-activated channels targeted to ON bipolar cells restore visual function in retinal degeneration. Nat Neurosci. 2008; 11(6):667-75. DOI: 10.1038/nn.2117. View

17.

Shire D, Kelly S, Chen J, Doyle P, Gingerich M, Cogan S . Development and implantation of a minimally invasive wireless subretinal neurostimulator. IEEE Trans Biomed Eng. 2009; 56(10):2502-11. PMC: 7444418. DOI: 10.1109/TBME.2009.2021401. View

18.

Nagel G, Szellas T, Huhn W, Kateriya S, Adeishvili N, Berthold P . Channelrhodopsin-2, a directly light-gated cation-selective membrane channel. Proc Natl Acad Sci U S A. 2003; 100(24):13940-5. PMC: 283525. DOI: 10.1073/pnas.1936192100. View

19.

Chader G, Weiland J, Humayun M . Artificial vision: needs, functioning, and testing of a retinal electronic prosthesis. Prog Brain Res. 2009; 175:317-32. DOI: 10.1016/S0079-6123(09)17522-2. View

20.

Hauswirth W, Aleman T, Kaushal S, Cideciyan A, Schwartz S, Wang L . Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther. 2008; 19(10):979-90. PMC: 2940541. DOI: 10.1089/hum.2008.107. View