{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:51:00Z","timestamp":1782280260967,"version":"3.54.5"},"posted":{"date-parts":[[2025,11,14]]},"group-title":"Neuroscience","reference-count":69,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T00:00:00Z","timestamp":1763078400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"crossref","award":["R01 EY029985"],"award-info":[{"award-number":["R01 EY029985"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  The ON visual pathway is initiated by the deactivation of mGluR6, coupled to the opening of TRPM1 channels in retinal ON-bipolar cell dendrites. Here, we show that a second metabotropic glutamate receptor, mGluR5, is localized with TRPM1 and mGluR6 in the dendrites of ON-bipolar cells. To examine the function of mGluR5, we performed electroretinogram (ERG) recordings and found that the amplitude of the b-wave, which is primarily a measure of ON-bipolar cell light-driven activity, is reduced in mGluR5 knock-out mice compared to wild type. In the mGluR5\n                  <jats:sup>-\/-<\/jats:sup>\n                  retina, we observed weaker mGluR6 immunofluorescence in the dendritic tips of ON-bipolar cells that could explain the smaller ERG b-wave. To observe the effect of mGluR5 without perturbing mGluR6 expression, wild type mice were injected with MTEP, an allosteric antagonist of mGluR5. MTEP increased the amplitude of the b-wave in response to dim stimuli and caused an inflection in the intensity-response plot for flashes in the mesopic range. In the brain, postsynaptic mGluR5 regulates presynaptic glutamate release via endocanabinoid-mediated retrograde signaling. Therefore, we tested the effect of the CB1 receptor antagonist, SR1417A, on the ERG and found that the b-wave was affected as by MTEP, including an inflection in the intensity-response. We further showed that the CB1 receptor agonist, ACEA, reversed the effects of MTEP. Together, our results indicate that mGluR5 plays a role in gain-control at the photoreceptor to ON-bipolar cell synapses, likely via an endocannabinoid-mediated retrograde feedback.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Significance Statement<\/jats:title>\n                  <jats:p>Light-ON stimuli are transmitted from photoreceptors to ON-bipolar cells via three pathways, which are used under different light intensities, from dim to bright light. For each pathway, glutamate is the neurotransmitter released by rods and cones, and the postsynaptic role of the mGluR6-TRPM1 signaling cascade in ON-bipolar cells is well studied, with defects known to cause congenital stationary night blindness. We show here that mGluR5 is also present in ON-bipolar cell dendrites and regulates synaptic transmission between photoreceptors and ON-bipolar cells. In particular, we find that mGluR5 facilitates the transition between the different photoreceptor to ON-bipolar cell pathways via mGluR5-controlled retrograde release of endocannabinoids.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.11.13.687902","type":"posted-content","created":{"date-parts":[[2025,11,15]],"date-time":"2025-11-15T01:50:14Z","timestamp":1763171414000},"source":"Crossref","is-referenced-by-count":0,"title":["The retinal light response is modulated by an mGluR5-mediated retrograde signal from ON-bipolar cells to photoreceptors"],"prefix":"10.64898","author":[{"given":"Catherine W.","family":"Morgans","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammie L.","family":"Haley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaoying","family":"Ren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian A. M.","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate L.","family":"Randall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert M.","family":"Duvoisin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025111708551228000_2025.11.13.687902v1.1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00142.2009"},{"key":"2025111708551228000_2025.11.13.687902v1.2","doi-asserted-by":"crossref","unstructured":"Agosto MA , Adeosun AAR , Kumar N , Wensel TG (2021) The mGluR6 ligand-binding domain, but not the C-terminal domain, is required for synaptic localization in retinal ON-bipolar cells. J Biol Chem 101418.","DOI":"10.1016\/j.jbc.2021.101418"},{"key":"2025111708551228000_2025.11.13.687902v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2017.06.017"},{"key":"2025111708551228000_2025.11.13.687902v1.4","doi-asserted-by":"crossref","first-page":"2146","DOI":"10.1021\/acschemneuro.7b00508","article-title":"Functional Relevance of Endocannabinoid-Dependent Synaptic Plasticity in the Central Nervous System","volume":"9","year":"2018","journal-title":"ACS Chem Neurosci"},{"key":"2025111708551228000_2025.11.13.687902v1.5","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7793.2000.00879.x"},{"key":"2025111708551228000_2025.11.13.687902v1.6","first-page":"699","article-title":"Roles of aspartate and glutamate in synaptic transmission in rabbit retina","volume":"53","year":"1985","journal-title":"I. Outer plexiform layer. J Neurophysiol"},{"key":"2025111708551228000_2025.11.13.687902v1.7","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4941-13.2014"},{"key":"2025111708551228000_2025.11.13.687902v1.8","doi-asserted-by":"publisher","DOI":"10.1002\/cne.20194"},{"key":"2025111708551228000_2025.11.13.687902v1.9","doi-asserted-by":"crossref","first-page":"4085","DOI":"10.1113\/JP281308","article-title":"Interactions of cone cannabinoid CB1 and dopamine D4 receptors increase day\/night difference in rod-cone gap junction coupling in goldfish retina","volume":"599","year":"2021","journal-title":"J Physiol"},{"key":"2025111708551228000_2025.11.13.687902v1.10","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1682-11.2011"},{"key":"2025111708551228000_2025.11.13.687902v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.09.002"},{"key":"2025111708551228000_2025.11.13.687902v1.12","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2009940117"},{"key":"2025111708551228000_2025.11.13.687902v1.13","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.1991.tb11429.x"},{"key":"2025111708551228000_2025.11.13.687902v1.14","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.37.1.205"},{"key":"2025111708551228000_2025.11.13.687902v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/372237a0"},{"key":"2025111708551228000_2025.11.13.687902v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/341536a0"},{"key":"2025111708551228000_2025.11.13.687902v1.17","doi-asserted-by":"publisher","DOI":"10.1021\/jm025570j"},{"key":"2025111708551228000_2025.11.13.687902v1.18","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)00158-6"},{"key":"2025111708551228000_2025.11.13.687902v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2006.04.034"},{"key":"2025111708551228000_2025.11.13.687902v1.20","doi-asserted-by":"publisher","DOI":"10.1096\/fj.10-163147"},{"key":"2025111708551228000_2025.11.13.687902v1.21","doi-asserted-by":"crossref","first-page":"109920","DOI":"10.1016\/j.isci.2024.109920","article-title":"Non-canonical type 1 cannabinoid receptor signaling regulates night visual processing in the inner rat retina","volume":"27","year":"2024","journal-title":"iScience"},{"key":"2025111708551228000_2025.11.13.687902v1.22","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.neuro.27.070203.144206"},{"key":"2025111708551228000_2025.11.13.687902v1.23","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(00)80442-0"},{"key":"2025111708551228000_2025.11.13.687902v1.24","doi-asserted-by":"crossref","first-page":"e13885","DOI":"10.14814\/phy2.13885","article-title":"A group I metabotropic glutamate receptor controls synaptic gain between rods and rod bipolar cells in the mouse retina","volume":"6","year":"2018","journal-title":"Physiol Rep"},{"key":"2025111708551228000_2025.11.13.687902v1.25","doi-asserted-by":"publisher","DOI":"10.1369\/0022155413483574"},{"key":"2025111708551228000_2025.11.13.687902v1.26","doi-asserted-by":"publisher","DOI":"10.1113\/JP271458"},{"key":"2025111708551228000_2025.11.13.687902v1.27","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s00441-007-0496-1","article-title":"Localization of metabotropic glutamate receptors in the outer plexiform layer of the goldfish retina","volume":"330","year":"2007","journal-title":"Cell Tissue Res"},{"key":"2025111708551228000_2025.11.13.687902v1.28","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00019.2008"},{"key":"2025111708551228000_2025.11.13.687902v1.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.jchemneu.2009.02.004"},{"key":"2025111708551228000_2025.11.13.687902v1.30","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1964-12.2012"},{"key":"2025111708551228000_2025.11.13.687902v1.31","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0912730107"},{"key":"2025111708551228000_2025.11.13.687902v1.32","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.17-06-02200.1997"},{"key":"2025111708551228000_2025.11.13.687902v1.33","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0712033105"},{"key":"2025111708551228000_2025.11.13.687902v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-19510-5"},{"key":"2025111708551228000_2025.11.13.687902v1.35","doi-asserted-by":"crossref","unstructured":"Li J , Choi J , Cheng X , Ma J , Pema S , Sanes JR , Mardon G , Frankfort BJ , Tran NM , Li Y , Chen R (2024) Comprehensive single-cell atlas of the mouse retina. iScience 27:109916.","DOI":"10.1016\/j.isci.2024.109916"},{"key":"2025111708551228000_2025.11.13.687902v1.36","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2013.265033"},{"key":"2025111708551228000_2025.11.13.687902v1.37","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.17-13-05196.1997"},{"key":"2025111708551228000_2025.11.13.687902v1.38","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.1996.tb01611.x"},{"key":"2025111708551228000_2025.11.13.687902v1.39","first-page":"2738","article-title":"A single-cell transcriptome atlas of the adult human retina","volume":"17","year":"2019","journal-title":"EMBO J"},{"key":"2025111708551228000_2025.11.13.687902v1.40","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.78.11.7185"},{"key":"2025111708551228000_2025.11.13.687902v1.41","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1146\/annurev-vision-102016-061338","article-title":"The Transduction Cascade in Retinal ON-Bipolar Cells: Signal Processing and Disease","volume":"3","year":"2017","journal-title":"Annu Rev Vis Sci"},{"key":"2025111708551228000_2025.11.13.687902v1.42","doi-asserted-by":"crossref","first-page":"113173","DOI":"10.1016\/j.celrep.2023.113173","article-title":"Rules and mechanisms governing G protein coupling selectivity of GPCRs","volume":"42","year":"2023","journal-title":"Cell Reports"},{"key":"2025111708551228000_2025.11.13.687902v1.43","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2024.107119"},{"key":"2025111708551228000_2025.11.13.687902v1.44","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2007.05867.x"},{"key":"2025111708551228000_2025.11.13.687902v1.45","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0908711106"},{"key":"2025111708551228000_2025.11.13.687902v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90151-1"},{"key":"2025111708551228000_2025.11.13.687902v1.47","doi-asserted-by":"publisher","DOI":"10.1046\/j.1460-9568.2002.01929.x"},{"key":"2025111708551228000_2025.11.13.687902v1.48","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0455-19.2019"},{"key":"2025111708551228000_2025.11.13.687902v1.49","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2655-11.2011"},{"key":"2025111708551228000_2025.11.13.687902v1.50","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.45.28612"},{"key":"2025111708551228000_2025.11.13.687902v1.51","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(04)00005-4"},{"key":"2025111708551228000_2025.11.13.687902v1.52","doi-asserted-by":"publisher","DOI":"10.1016\/S0028-3908(99)00092-1"},{"key":"2025111708551228000_2025.11.13.687902v1.53","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(88)90610-7"},{"key":"2025111708551228000_2025.11.13.687902v1.54","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1017\/S0952523806232073","article-title":"Immunolocalization of metabotropic glutamate receptors 1 and 5 in the synaptic layers of the chicken retina","volume":"23","year":"2006","journal-title":"Vis Neurosci"},{"key":"2025111708551228000_2025.11.13.687902v1.55","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.07.054"},{"key":"2025111708551228000_2025.11.13.687902v1.56","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0132-09.2009"},{"key":"2025111708551228000_2025.11.13.687902v1.57","doi-asserted-by":"publisher","DOI":"10.1016\/S0028-3908(03)00053-4"},{"key":"2025111708551228000_2025.11.13.687902v1.58","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-33592-8"},{"key":"2025111708551228000_2025.11.13.687902v1.59","doi-asserted-by":"crossref","first-page":"112247","DOI":"10.1016\/j.celrep.2023.112247","article-title":"Somatic and terminal CB1 receptors are differentially coupled to voltage-gated sodium channels in neocortical neurons","volume":"42","year":"2023","journal-title":"Cell Rep"},{"key":"2025111708551228000_2025.11.13.687902v1.60","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.25.14565"},{"key":"2025111708551228000_2025.11.13.687902v1.61","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.19-07-02568.1999"},{"key":"2025111708551228000_2025.11.13.687902v1.62","doi-asserted-by":"crossref","unstructured":"Tarhan L , Bistline J , Chang J , Galloway B , Hanna E , Weitz E (2023) Single Cell Portal: an interactive home for single-cell genomics data. bioRxiv","DOI":"10.1101\/2023.07.13.548886"},{"key":"2025111708551228000_2025.11.13.687902v1.63","doi-asserted-by":"publisher","DOI":"10.1002\/1096-9861(20000731)423:3<402::AID-CNE4>3.0.CO;2-E"},{"key":"2025111708551228000_2025.11.13.687902v1.64","doi-asserted-by":"crossref","unstructured":"Varma N , Carlson GC , Ledent C , Alger BE (2001) Metabotropic glutamate receptors drive the endocannabinoid system in hippocampus. J Neurosci 21:RC188.","DOI":"10.1523\/JNEUROSCI.21-24-j0003.2001"},{"key":"2025111708551228000_2025.11.13.687902v1.65","doi-asserted-by":"crossref","first-page":"100164","DOI":"10.1016\/j.xgen.2022.100164","article-title":"Single-cell multiome of the human retina and deep learning nominate causal variants in complex eye diseases","volume":"2","year":"2022","journal-title":"Cell Genom"},{"key":"2025111708551228000_2025.11.13.687902v1.66","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.4442-08.2009"},{"key":"2025111708551228000_2025.11.13.687902v1.67","doi-asserted-by":"crossref","unstructured":"Xiao B , Tu JC , Worley PF (2000) Homer: a link between neural activity and glutamate receptor function. Curr Opin Neurobiol 10:370\u2013374.","DOI":"10.1016\/S0959-4388(00)00087-8"},{"key":"2025111708551228000_2025.11.13.687902v1.68","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00933.2011"},{"key":"2025111708551228000_2025.11.13.687902v1.69","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9861(19991206)415:1<80::AID-CNE6>3.0.CO;2-H"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.11.13.687902","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:00:29Z","timestamp":1782277229000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.11.13.687902"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,14]]},"references-count":69,"URL":"https:\/\/doi.org\/10.1101\/2025.11.13.687902","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1523\/JNEUROSCI.2277-24.2025","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2025,11,14]]},"subtype":"preprint"}}