{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T12:29:21Z","timestamp":1785414561395,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,25]]},"group-title":"Neuroscience","reference-count":50,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T00:00:00Z","timestamp":1784937600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"award":["EY030554"],"award-info":[{"award-number":["EY030554"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["EY003039"],"award-info":[{"award-number":["EY003039"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/00zj09521","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Purpose<\/jats:title>\n                  <jats:p>\n                    Synaptic dysfunction and neurite remodeling are early features of many inherited retinal diseases, but whether synaptic function can be restored after circuit remodeling remains unclear. We evaluated the therapeutic potential of adeno-associated virus (AAV)-mediated \u03b12\u03b44 gene supplementation in a mouse model of\n                    <jats:italic>CACNA2D4<\/jats:italic>\n                    -associated retinal synaptopathy.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>AAV8-GRK1-\u03b12\u03b44 was delivered by subretinal injection to \u03b12\u03b44 knockout mice at neonatal, young adult, or middle-aged adult stages. Retinal function was assessed by electroretinography. Synaptic organization and circuit remodeling were evaluated by immunohistochemistry.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>AAV-mediated \u03b12\u03b44 expression restored synaptic localization of Cav1.4, ELFN proteins, and mGluR6 at all treatment ages. However, circuit structure and functional rescue were age- and circuit-dependent. Neonatal treatment restored rod and cone transmission and prevented photoreceptor terminal retraction and bipolar cell dendritic sprouting. Rescue in young adults improved rod and cone circuit function but did not reverse neurite remodeling. Rescue in middle-aged mice restored cone but not rod transmission. Notably, neonatal treatment produced the highest proportion of synapses within synaptic layer, whereas adult treatment generated increasing ectopic synapses in nuclear layer.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    Photoreceptor synaptic assembly remains plastic in remodeled retinas and can be restored by \u03b12\u03b44 supplementation. However, rescue efficacy is influenced by age and circuits with rod circuits exhibiting a narrower therapeutic window. Synaptic molecular reassembly can occur without neurite restoration. These findings establish \u03b12\u03b44 gene therapy as a promising treatment for\n                    <jats:italic>CACNA2D4<\/jats:italic>\n                    -associated retinal synaptopathy and reveal distinct intervention windows for synaptic assembly, neurite remodeling, and rod versus cone circuit recovery.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.07.21.739956","type":"posted-content","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:31:11Z","timestamp":1785130271000},"source":"Crossref","is-referenced-by-count":0,"title":["AAV-mediated age- and circuit-dependent restoration of photoreceptor synaptic structure and function in \u03b12\u03b44-associated retinal synaptopathy"],"prefix":"10.64898","author":[{"given":"Trong Thuan","family":"Ung","sequence":"first","affiliation":[{"name":"Department of Optometry and Vision Science, The University of Alabama at Birmingham, Birmingham, AL 35249 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