{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T17:21:25Z","timestamp":1789147285971,"version":"build-2803163510"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T00:00:00Z","timestamp":1746748800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>Glycine, along with GABA, constitutes the major inhibitory neurotransmitter in the central nervous system. In the retina, glycinergic neurotransmission is primarily used by amacrine cells that are involved in the lateral processing of visual stimuli in the inner retina. We have previously shown that the high-affinity glycine transporter 1 (GlyT1), that is commonly used as a reliable marker for glycinergic amacrine cells in the retina, is essential for glycinergic neurotransmission by these cells. Abolishment of retinal GlyT1 expression results in a breakdown of glycinergic neurotransmission by AII amacrine cells, but most likely also by other glycinergic amacrine cell populations. However, the impact of loss of glycinergic neurotransmission on retinal signal processing and visually guided behavior, has not yet been elucidated. In this study, the effects of loss of retinal GlyT1 expression in glycinergic amacrine cells on the optomotor reflex and on the photopic and scotopic electroretinogram (ERG) responses were analyzed. We show that retinal GlyT1-deficient mice have normal optomotor responses to rotating black and white stripes. When stimuli with sawtooth luminance profiles were used, thereby differentially activating ON and OFF pathways, the GlyT1 deficient mice showed facilitated responses to ON preferring stimuli, whereas responses to OFF preferring stimuli were unchanged. These findings were corroborated by ERG recordings that showed undistinguishable responses after flash stimulation but revealed differences in the differential processing of ON and OFF preferring stimuli. To determine if the function of retinal GlyT1 is conserved in humans, we analyzed ERG recordings from a patient diagnosed with GlyT1 encephalopathy. We show that GlyT1 deficiency results in marked ERG changes, characterized by an almost complete loss of the \u201cphotopic hill\u201d phenomenon, a hill-like appearance of the relationship between the b-wave amplitude and log light stimulus strength under background illumination conditions, and reductions in the ERG oscillatory potentials in the dark- and light-adapted states. Both findings are consistent with an altered interaction between ON- and OFF pathways in the retina. Taken together our data show that glycinergic neurotransmission in the retina has important functions in retinal ON and OFF processing both in mice and humans.<\/jats:p>","DOI":"10.3389\/fnmol.2025.1564870","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T05:36:39Z","timestamp":1746768999000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Changes in glycinergic neurotransmission alter mammalian retinal information processing"],"prefix":"10.3389","volume":"18","author":[{"given":"Anneka","family":"Joachimsthaler","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Hauf","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Armbruster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiri","family":"Zayit-Soudry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Efrat","family":"Naaman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ido","family":"Perlman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rina","family":"Leibu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alina","family":"Kurolap","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hagit","family":"Baris Feldman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Kremers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volker","family":"Eulenburg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,9]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1263","DOI":"10.1007\/s00439-016-1719-x","article-title":"Mutation in SLC6A9 encoding a glycine transporter causes a novel form of non-ketotic hyperglycinemia in humans","volume":"135","author":"Alfadhel","year":"2016","journal-title":"Hum. 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Dis."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1038\/nature16468","article-title":"The functional diversity of retinal ganglion cells in the mouse","volume":"529","author":"Baden","year":"2016","journal-title":"Nature"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1016\/S1350-9462(00)00031-8","article-title":"Rod vision: pathways and processing in the mammalian retina","volume":"20","author":"Bloomfield","year":"2001","journal-title":"Prog. Retin. Eye Res."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"1239","DOI":"10.1016\/0042-6989(92)90218-8","article-title":"Sawtooth contrast sensitivity: effects of mean illuminance and low temporal frequencies","volume":"32","author":"Bowen","year":"1992","journal-title":"Vis. 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Res."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1007\/s10633-009-9194-5","article-title":"Electrophysiological deficits in the retina of the DBA\/2J mouse","volume":"119","author":"Harazny","year":"2009","journal-title":"Doc. Ophthalmol."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"104813","DOI":"10.1016\/j.neuint.2020.104813","article-title":"GlyT1 encephalopathy: characterization of presumably disease causing GlyT1 mutations","volume":"139","author":"Hauf","year":"2020","journal-title":"Neurochem. Int."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1002\/dvg.20640","article-title":"Generation of a mouse line expressing Cre recombinase in glycinergic interneurons","volume":"48","author":"Ishihara","year":"2010","journal-title":"Genesis"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"110410","DOI":"10.1016\/j.celrep.2022.110410","article-title":"Gain control by sparse, ultra-slow glycinergic synapses","volume":"38","author":"Jain","year":"2022","journal-title":"Cell Rep."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"8936","DOI":"10.1523\/JNEUROSCI.18-21-08936.1998","article-title":"The major cell populations of the mouse retina","volume":"18","author":"Jeon","year":"1998","journal-title":"J. Neurosci."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"2152","DOI":"10.1167\/iovs.18-26356","article-title":"Mouse cones adapt fast, rods slowly in vivo","volume":"60","author":"Joachimsthaler","year":"2019","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1997","DOI":"10.1016\/0042-6989(93)90023-P","article-title":"Responses of macaque ganglion cells and human observers to compound periodic waveforms","volume":"33","author":"Kremers","year":"1993","journal-title":"Vis. Res."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"A170","DOI":"10.1364\/JOSAA.31.00A170","article-title":"Incremental and decremental L- and M-cone driven ERG responses: II. Sawtooth stimulation","volume":"31","author":"Kremers","year":"2014","journal-title":"J. Opt. Soc. Am. A Opt. Image Sci. Vis."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1172","DOI":"10.1016\/j.ajhg.2016.09.004","article-title":"Loss of Glycine transporter 1 causes a subtype of Glycine encephalopathy with arthrogryposis and mildly elevated cerebrospinal fluid Glycine","volume":"99","author":"Kurolap","year":"2016","journal-title":"Am. J. Hum. Genet."},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1523\/JNEUROSCI.13-03-01001.1993","article-title":"Macaque ganglion cell responses to stimuli that elicit hyperacuity in man: detection of small displacements","volume":"13","author":"Lee","year":"1993","journal-title":"J. Neurosci."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1007\/PL00000899","article-title":"The glycinergic inhibitory synapse","volume":"58","author":"Legendre","year":"2001","journal-title":"Cell. Mol. 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Physiol."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"5142","DOI":"10.1038\/s41467-023-40527-z","article-title":"A circuit suppressing retinal drive to the optokinetic system during fast image motion","volume":"14","author":"Mani","year":"2023","journal-title":"Nat. Commun."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"4136","DOI":"10.1523\/JNEUROSCI.4274-07.2008","article-title":"Disinhibition combines with excitation to extend the operating range of the OFF visual pathway in daylight","volume":"28","author":"Manookin","year":"2008","journal-title":"J. Neurosci."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1016\/S0014-4835(89)80038-7","article-title":"Effects of 2-amino-4-phosphonobutyric acid (APB) and glycine on the oscillatory potentials of the rat electroretinogram","volume":"49","author":"Matthews","year":"1989","journal-title":"Exp. Eye Res."},{"key":"ref35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s10633-014-9473-7","article-title":"ISCEV standard for full-field clinical electroretinography (2015 update)","volume":"130","author":"McCulloch","year":"2015","journal-title":"Doc. Ophthalmol."},{"key":"ref36","doi-asserted-by":"publisher","first-page":"4039","DOI":"10.1242\/jcs.175687","article-title":"Photoreceptors at a glance","volume":"128","author":"Molday","year":"2015","journal-title":"J. Cell Sci."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"237","DOI":"10.1007\/s10633-012-9323-4","article-title":"On- and off-response ERGs elicited by sawtooth stimuli in normal subjects and glaucoma patients","volume":"124","author":"Pangeni","year":"2012","journal-title":"Doc. Ophthalmol."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"2628","DOI":"10.1046\/j.1471-4159.1998.70062628.x","article-title":"Transport is the primary determinant of glycine content in retinal neurons","volume":"70","author":"Pow","year":"1998","journal-title":"J. Neurochem."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1017\/S0952523800171019","article-title":"Expression of glycine and the glycine transporter Glyt-1 in the developing rat retina","volume":"17","author":"Pow","year":"2000","journal-title":"Vis. Neurosci."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1556\/ABiol.53.2002.1-2.14","article-title":"Electrophysiological evidence for push-pull interactions in the inner retina of turtle","volume":"53","author":"Rabl","year":"2002","journal-title":"Acta Biol. Hung."},{"key":"ref41","first-page":"231","article-title":"Cone-dominated ERG luminance-response function: The Photopic Hill revisited","volume":"104","author":"Regus-Leidig","year":"2014","journal-title":"Doc Ophthalmol."},{"key":"ref9002","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1023\/A:1015265812018","article-title":"Cone-dominated ERG luminance-response function: The Photopic Hill revisited","volume":"104","author":"Rufiange","year":"2002","journal-title":"Doc Ophthalmol."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1113\/jphysiol.2002.019703","article-title":"The scotopic threshold response of the dark-adapted electroretinogram of the mouse","volume":"543","author":"Saszik","year":"2002","journal-title":"J. Physiol."},{"key":"ref43","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.1016\/j.neuron.2016.04.041","article-title":"A central role for mixed acetylcholine\/GABA transmission in direction coding in the retina","volume":"90","author":"Sethuramanujam","year":"2016","journal-title":"Neuron"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"4312","DOI":"10.1523\/JNEUROSCI.3066-18.2019","article-title":"Simulated saccadic stimuli suppress ON-type direction-selective retinal ganglion cells via Glycinergic inhibition","volume":"39","author":"Sivyer","year":"2019","journal-title":"J. Neurosci."},{"key":"ref45","doi-asserted-by":"publisher","first-page":"2130","DOI":"10.1016\/j.cub.2022.03.054","article-title":"Distinct inhibitory pathways control velocity and directional tuning in the mouse retina","volume":"32","author":"Summers","year":"2022","journal-title":"Curr. Biol."},{"key":"ref46","doi-asserted-by":"publisher","first-page":"1365","DOI":"10.1126\/science.160.3834.1365","article-title":"Optomotor responses to monocular stimulation: relation to visual system organization","volume":"160","author":"Tauber","year":"1968","journal-title":"Science"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"712","DOI":"10.1111\/j.1755-3768.1980.tb06684.x","article-title":"Further studies of the chemical sensitivity of the oscillatory potentials of the electroretinogram (ERG) I. GABA- and glycine antagonists","volume":"58","author":"Wachtmeister","year":"1980","journal-title":"Acta Ophthalmol."},{"key":"ref9001","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1007\/BF00154382","article-title":"The photopic hill: A new phenomenon of the light adapted electroretinogram","volume":"80","author":"Wali","year":"1992","journal-title":"Doc Ophthalmol."},{"key":"ref48","doi-asserted-by":"publisher","first-page":"6","DOI":"10.3389\/neuro.02.006.2009","article-title":"Glycinergic transmission in the mammalian retina","volume":"2","author":"W\u00e4ssle","year":"2009","journal-title":"Front. Mol. Neurosci."},{"key":"ref49","doi-asserted-by":"publisher","first-page":"5177","DOI":"10.1523\/JNEUROSCI.0471-20.2020","article-title":"Sanes, mouse retinal cell atlas: Molecular identification of over sixty amacrine cell types","volume":"40","author":"Yan","year":"2020","journal-title":"J Neurosci"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"771","DOI":"10.1016\/S0896-6273(01)00316-6","article-title":"A key role of starburst amacrine cells in originating retinal directional selectivity and optokinetic eye movement","volume":"30","author":"Yoshida","year":"2001","journal-title":"Neuron"}],"container-title":["Frontiers in Molecular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2025.1564870\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T05:36:40Z","timestamp":1746769000000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2025.1564870\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,9]]},"references-count":52,"alternative-id":["10.3389\/fnmol.2025.1564870"],"URL":"https:\/\/doi.org\/10.3389\/fnmol.2025.1564870","relation":{},"ISSN":["1662-5099"],"issn-type":[{"value":"1662-5099","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,9]]},"article-number":"1564870"}}