{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T21:01:36Z","timestamp":1791493296558,"version":"4.3.4"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,9,19]],"date-time":"2019-09-19T00:00:00Z","timestamp":1568851200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,9,19]],"date-time":"2019-09-19T00:00:00Z","timestamp":1568851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Photopharmacology has yielded compounds that have potential to restore impaired visual responses resulting from outer retinal degeneration diseases such as retinitis pigmentosa. Here we evaluate two photoswitchable azobenzene ion channel blockers, DAQ and DAA for vision restoration. DAQ exerts its effect primarily on RGCs, whereas DAA induces light-dependent spiking primarily through amacrine cell\u00a0activation. Degeneration-induced local field potentials remain a major challenge common to all vision restoration approaches. These 5\u201310\u2009Hz rhythmic potentials increase the background firing rate of retinal ganglion cells (RGCs) and overlay the stimulated response, thereby reducing signal-to-noise ratio. Along with the bipolar cell-selective photoswitch DAD and second-generation RGC-targeting photoswitch PhENAQ, we investigated the effects of DAA and DAQ on rhythmic local field potentials (LFPs) occurring in the degenerating retina. We found that photoswitches targeting neurons upstream of RGCs, DAA (amacrine cells) and DAD (bipolar cells) suppress the frequency of LFPs, while DAQ and PhENAQ (RGCs) had negligible effects on frequency or spectral power of LFPs. Taken together, these results demonstrate remarkable diversity of cell-type specificity of photoswitchable channel blockers in the retina and suggest that specific compounds may counter rhythmic LFPs to produce superior signal-to-noise characteristics in vision restoration.<\/jats:p>","DOI":"10.1038\/s41598-019-49999-w","type":"journal-article","created":{"date-parts":[[2019,9,19]],"date-time":"2019-09-19T10:04:13Z","timestamp":1568887453000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Photopharmacologic Vision Restoration Reduces Pathological Rhythmic Field Potentials in Blind Mouse Retina"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6921-6537","authenticated-orcid":false,"given":"Katharina","family":"H\u00fcll","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler","family":"Benster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael B.","family":"Manookin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6782-6056","authenticated-orcid":false,"given":"Dirk","family":"Trauner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell N.","family":"Van Gelder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Laprell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,9,19]]},"reference":[{"key":"49999_CR1","doi-asserted-by":"publisher","first-page":"359","DOI":"10.1038\/s41586-018-0076-4","volume":"557","author":"B Roska","year":"2018","unstructured":"Roska, B. & Sahel, J. A. Restoring vision. Nature 557, 359\u2013367 (2018).","journal-title":"Nature"},{"key":"49999_CR2","doi-asserted-by":"publisher","first-page":"10748","DOI":"10.1021\/acs.chemrev.7b00723","volume":"118","author":"I Tochitsky","year":"2018","unstructured":"Tochitsky, I., Kienzler, M. A., Isacoff, E. & Kramer, R. H. Restoring Vision to the Blind with Chemical Photoswitches. Chem. Rev. 118, 10748\u201310773 (2018).","journal-title":"Chem. Rev."},{"key":"49999_CR3","doi-asserted-by":"publisher","DOI":"10.1038\/srep45487","volume":"7","author":"I Tochitsky","year":"2017","unstructured":"Tochitsky, I., Trautman, J., Gallerani, N., Malis, J. G. & Kramer, R. H. Restoring visual function to the blind retina with a potent, safe and long-lasting photoswitch. Sci. Rep. 7, 45487 (2017).","journal-title":"Sci. Rep."},{"key":"49999_CR4","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.neuron.2012.05.022","volume":"75","author":"A Polosukhina","year":"2012","unstructured":"Polosukhina, A. et al. Photochemical Restoration of Visual Responses in Blind Mice. Neuron 75, 271\u2013282 (2012).","journal-title":"Neuron"},{"key":"49999_CR5","doi-asserted-by":"publisher","first-page":"800","DOI":"10.1016\/j.neuron.2014.01.003","volume":"81","author":"I Tochitsky","year":"2014","unstructured":"Tochitsky, I. et al. Restoring Visual Function to Blind Mice with a Photoswitch that Exploits Electrophysiological Remodeling of Retinal Ganglion Cells. Neuron 81, 800\u2013813 (2014).","journal-title":"Neuron"},{"key":"49999_CR6","doi-asserted-by":"crossref","unstructured":"Laprell, L. et al. Photopharmacological control of bipolar cells restores visual function in blind mice. J. Clin. Invest. 127 (2017).","DOI":"10.1172\/JCI92156"},{"key":"49999_CR7","doi-asserted-by":"publisher","first-page":"10710","DOI":"10.1021\/acs.chemrev.8b00037","volume":"118","author":"K H\u00fcll","year":"2018","unstructured":"H\u00fcll, K., Morstein, J. & Trauner, D. In Vivo Photopharmacology. Chem. Rev. 118, 10710\u201310747 (2018).","journal-title":"Chem. Rev."},{"key":"49999_CR8","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1385\/MN:28:2:139","volume":"28","author":"RE Marc","year":"2003","unstructured":"Marc, R. E. & Jones, B. W. Retinal Remodeling in Inherited Photoreceptor Degenerations. Mol. Neurobiol. 28, 139\u2013148 (2003).","journal-title":"Mol. Neurobiol."},{"key":"49999_CR9","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/cne.10703","volume":"464","author":"BW Jones","year":"2003","unstructured":"Jones, B. W. et al. Retinal remodeling triggered by photoreceptor degenerations. J. Comp. Neurol. 464, 1\u201316 (2003).","journal-title":"J. Comp. Neurol."},{"key":"49999_CR10","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1016\/j.exer.2016.03.018","volume":"150","author":"BW Jones","year":"2016","unstructured":"Jones, B. W. et al. Retinal remodeling in human retinitis pigmentosa. Exp. Eye Res. 150, 149\u2013165 (2016).","journal-title":"Exp. Eye Res."},{"key":"49999_CR11","doi-asserted-by":"publisher","first-page":"1491","DOI":"10.1152\/jn.00437.2014","volume":"112","author":"H Choi","year":"2014","unstructured":"Choi, H. et al. Intrinsic bursting of AII amacrine cells underlies oscillations in the rd1 mouse retina. J. Neurophysiol. 112, 1491\u2013504 (2014).","journal-title":"J. Neurophysiol."},{"key":"49999_CR12","doi-asserted-by":"publisher","first-page":"e86253","DOI":"10.1371\/journal.pone.0086253","volume":"9","author":"DJ Margolis","year":"2014","unstructured":"Margolis, D. J., Gartland, A. J., Singer, J. H. & Detwiler, P. B. Network Oscillations Drive Correlated Spiking of ON and OFF Ganglion Cells in the rd1 Mouse Model of Retinal Degeneration. PLoS One 9, e86253 (2014).","journal-title":"PLoS One"},{"key":"49999_CR13","doi-asserted-by":"publisher","first-page":"3002","DOI":"10.1152\/jn.00704.2010","volume":"105","author":"SF Stasheff","year":"2011","unstructured":"Stasheff, S. F., Shankar, M. & Andrews, M. P. Developmental time course distinguishes changes in spontaneous and light-evoked retinal ganglion cell activity in rd1 and rd10 mice. J. Neurophysiol. 105, 3002\u20133009 (2011).","journal-title":"J. Neurophysiol."},{"key":"49999_CR14","doi-asserted-by":"publisher","first-page":"415","DOI":"10.4196\/kjpp.2011.15.6.415","volume":"15","author":"YS Goo","year":"2011","unstructured":"Goo, Y. S. et al. Spontaneous oscillatory rhythm in retinal activities of two retinal degeneration (rd1 and rd10) mice. Korean J. Physiol. Pharmacol. 15, 415\u2013422 (2011).","journal-title":"Korean J. Physiol. Pharmacol."},{"key":"49999_CR15","doi-asserted-by":"publisher","first-page":"1079","DOI":"10.1088\/0967-3334\/28\/9\/009","volume":"28","author":"JH Ye","year":"2007","unstructured":"Ye, J. H. & Goo, Y. S. The slow wave component of retinal activity in rd\/rd mice recorded with a multi-electrode array. Physiol. Meas. 28, 1079\u201388 (2007).","journal-title":"Physiol. Meas."},{"key":"49999_CR16","doi-asserted-by":"publisher","first-page":"330","DOI":"10.3389\/fncel.2015.00330","volume":"9","author":"JM Barrett","year":"2015","unstructured":"Barrett, J. M., Degenaar, P. & Sernagor, E. Blockade of pathological retinal ganglion cell hyperactivity improves optogenetically evoked light responses in rd1 mice. Front. Cell. Neurosci. 9, 330 (2015).","journal-title":"Front. Cell. Neurosci."},{"key":"49999_CR17","doi-asserted-by":"crossref","first-page":"6610","DOI":"10.1016\/S0021-9258(18)53294-4","volume":"268","author":"EA Meade","year":"1993","unstructured":"Meade, E. A., Smith, W. L. & DeWitt, D. L. Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. J. Biol. Chem. 268, 6610\u20134 (1993).","journal-title":"J. Biol. Chem."},{"key":"49999_CR18","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1021\/cn200037p","volume":"2","author":"A Mourot","year":"2011","unstructured":"Mourot, A. et al. Tuning Photochromic Ion Channel Blockers. ACS Chem. Neurosci. 2, 536\u2013543 (2011).","journal-title":"ACS Chem. Neurosci."},{"key":"49999_CR19","unstructured":"Dipin, D. & Evans, D. Evans pKa Table. http:\/\/evans.rc.fas.harvard.edu\/pdf\/evans_pKa_table.pdf."},{"key":"49999_CR20","doi-asserted-by":"publisher","unstructured":"Mitra, P. & Bokil, H. Observed Brain Dynamics, https:\/\/doi.org\/10.1093\/acprof:oso\/9780195178081.001.0001 (Oxford University Press, 2007).","DOI":"10.1093\/acprof:oso\/9780195178081.001.0001"},{"key":"49999_CR21","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1016\/j.jneumeth.2010.06.020","volume":"192","author":"H Bokil","year":"2010","unstructured":"Bokil, H., Andrews, P., Kulkarni, J. E., Mehta, S. & Mitra, P. P. Chronux: a platform for analyzing neural signals. J. Neurosci. Methods 192, 146\u201351 (2010).","journal-title":"J. Neurosci. Methods"},{"key":"49999_CR22","doi-asserted-by":"publisher","first-page":"5017","DOI":"10.1167\/iovs.05-1468","volume":"47","author":"B Chang","year":"2006","unstructured":"Chang, B. et al. Cone Photoreceptor Function Loss-3, a Novel Mouse Model of Achromatopsia Due to a Mutation in Gnat2. Investig. Opthalmology Vis. Sci. 47, 5017 (2006).","journal-title":"Investig. Opthalmology Vis. Sci."},{"key":"49999_CR23","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1016\/S0042-6989(01)00214-0","volume":"42","author":"AL Lyubarsky","year":"2002","unstructured":"Lyubarsky, A. L. et al. Functionally rodless mice: transgenic models for the investigation of cone function in retinal disease and therapy. Vision Res. 42, 401\u201315 (2002).","journal-title":"Vision Res."},{"key":"49999_CR24","doi-asserted-by":"publisher","first-page":"2213","DOI":"10.1126\/science.1076848","volume":"298","author":"S Panda","year":"2002","unstructured":"Panda, S. et al. Melanopsin (Opn4) requirement for normal light-induced circadian phase shifting. Science 298, 2213\u20136 (2002).","journal-title":"Science"},{"key":"49999_CR25","doi-asserted-by":"publisher","first-page":"5000","DOI":"10.1523\/JNEUROSCI.5800-10.2011","volume":"31","author":"J Borowska","year":"2011","unstructured":"Borowska, J., Trenholm, S. & Awatramani, G. B. An intrinsic neural oscillator in the degenerating mouse retina. J. Neurosci. 31, 5000\u20135012 (2011).","journal-title":"J. Neurosci."},{"key":"49999_CR26","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.neuron.2016.08.038","volume":"92","author":"I Tochitsky","year":"2016","unstructured":"Tochitsky, I. et al. How Azobenzene Photoswitches Restore Visual Responses to the Blind Retina. Neuron 92, 100\u2013113 (2016).","journal-title":"Neuron"},{"key":"49999_CR27","doi-asserted-by":"publisher","first-page":"e106047","DOI":"10.1371\/journal.pone.0106047","volume":"9","author":"J Menzler","year":"2014","unstructured":"Menzler, J., Channappa, L. & Zeck, G. Rhythmic Ganglion Cell Activity in Bleached and Blind Adult Mouse Retinas. PLoS One 9, e106047 (2014).","journal-title":"PLoS One"},{"key":"49999_CR28","doi-asserted-by":"publisher","first-page":"444","DOI":"10.3389\/fncel.2015.00444","volume":"9","author":"T Euler","year":"2015","unstructured":"Euler, T. & Schubert, T. Multiple Independent Oscillatory Networks in the Degenerating Retina. Front. Cell. Neurosci. 9, 444 (2015).","journal-title":"Front. Cell. Neurosci."},{"key":"49999_CR29","doi-asserted-by":"publisher","first-page":"2280","DOI":"10.1523\/JNEUROSCI.4238-10.2011","volume":"31","author":"J Menzler","year":"2011","unstructured":"Menzler, J. & Zeck, G. Network Oscillations in Rod-Degenerated Mouse Retinas. J. Neurosci. 31, 2280\u20132291 (2011).","journal-title":"J. Neurosci."},{"key":"49999_CR30","doi-asserted-by":"publisher","first-page":"8","DOI":"10.3389\/fnsys.2012.00008","volume":"6","author":"CW Yee","year":"2012","unstructured":"Yee, C. W., Toychiev, A. H. & Sagdullaev, B. T. Network deficiency exacerbates impairment in a mouse model of retinal degeneration. Front. Syst. Neurosci. 6, 8 (2012).","journal-title":"Front. Syst. Neurosci."},{"key":"49999_CR31","doi-asserted-by":"publisher","first-page":"13972","DOI":"10.1523\/JNEUROSCI.2399-13.2013","volume":"33","author":"AH Toychiev","year":"2013","unstructured":"Toychiev, A. H., Ivanova, E., Yee, C. W. & Sagdullaev, B. T. Block of gap junctions eliminates aberrant activity and restores light responses during retinal degeneration. J. Neurosci. 33, 13972\u20137 (2013).","journal-title":"J. Neurosci."},{"key":"49999_CR32","doi-asserted-by":"publisher","first-page":"e1002143","DOI":"10.1371\/journal.pbio.1002143","volume":"13","author":"M van Wyk","year":"2015","unstructured":"van Wyk, M., Pielecka-Fortuna, J., L\u00f6wel, S. & Kleinlogel, S. Restoring the ON Switch in Blind Retinas: Opto-mGluR6, a Next-Generation, Cell-Tailored Optogenetic Tool. PLoS Biol. 13, e1002143 (2015).","journal-title":"PLoS Biol."},{"key":"49999_CR33","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1126\/science.1190897","volume":"329","author":"V Busskamp","year":"2010","unstructured":"Busskamp, V. et al. Genetic reactivation of cone photoreceptors restores visual responses in retinitis pigmentosa. Science 329, 413\u2013417 (2010).","journal-title":"Science"},{"key":"49999_CR34","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1021\/acschemneuro.5b00234","volume":"7","author":"L Laprell","year":"2016","unstructured":"Laprell, L. et al. Restoring Light Sensitivity in Blind Retinae Using a Photochromic AMPA Receptor Agonist. ACS Chem. Neurosci. 7, 15\u201320 (2016).","journal-title":"ACS Chem. Neurosci."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-49999-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-49999-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-49999-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T13:44:26Z","timestamp":1671284666000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-49999-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,19]]},"references-count":34,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["49999"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-49999-w","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,19]]},"assertion":[{"value":"12 March 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 September 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 September 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"13561"}}