{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T16:09:05Z","timestamp":1753891745887,"version":"3.41.2"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,5,12]],"date-time":"2023-05-12T00:00:00Z","timestamp":1683849600000},"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. Synaptic Neurosci."],"abstract":"<jats:p>Cannabis exposure during gestation evokes significant molecular modifications to neurodevelopmental programs leading to neurophysiological and behavioral abnormalities in humans. The main neuronal receptor for \u0394<jats:sup>9<\/jats:sup>-tetrahydrocannabinol (THC) is the type-1 cannabinoid receptor CB<jats:sub>1<\/jats:sub>R, one of the most abundant G-protein-coupled receptors in the nervous system. While THC is the major psychoactive phytocannabinoid, endocannabinoids (eCBs) are the endogenous ligands of CB<jats:sub>1<\/jats:sub>R and are known to act as retrograde messengers to modulate synaptic plasticity at different time scales in the adult brain. Accumulating evidence indicates that eCB signaling through activation of CB<jats:sub>1<\/jats:sub>R plays a central role in neural development. During development, most CB<jats:sub>1<\/jats:sub>R localized to axons of projection neurons, and in mice eCB signaling impacts axon fasciculation. Understanding of eCB-mediated structural plasticity during development, however, requires the identification of the precise spatial and temporal dynamics of CB<jats:sub>1<\/jats:sub>R-mediated modifications at the level of individual neurons in the intact brain. Here, the cell-autonomous role of CB<jats:sub>1<\/jats:sub>R and the effects of CB<jats:sub>1<\/jats:sub>R-mediated eCB signaling were investigated using targeted single-cell knockdown and pharmacologic treatments in <jats:italic>Xenopus<\/jats:italic>. We imaged axonal arbors of retinal ganglion cells (RGCs) in real time following downregulation of CB<jats:sub>1<\/jats:sub>R <jats:italic>via<\/jats:italic> morpholino (MO) knockdown. We also analyzed RGC axons with altered eCB signaling following treatment with URB597, a selective inhibitor of the enzyme that degrades Anandamide (AEA), or JZL184, an inhibitor of the enzyme that blocks 2-Arachidonoylglycerol (2-AG) hydrolysis, at two distinct stages of retinotectal development. Our results demonstrate that CB<jats:sub>1<\/jats:sub>R knockdown impacts RGC axon branching at their target and that differential 2-AG and AEA-mediated eCB signaling contributes to presynaptic structural connectivity at the time that axons terminate and when retinotectal synaptic connections are made. Altering CB<jats:sub>1<\/jats:sub>R levels through CB<jats:sub>1<\/jats:sub>R MO knockdown similarly impacted dendritic morphology of tectal neurons, thus supporting both pre- and postsynaptic cell-autonomous roles for CB<jats:sub>1<\/jats:sub>R-mediated eCB signaling.<\/jats:p>","DOI":"10.3389\/fnsyn.2023.1176864","type":"journal-article","created":{"date-parts":[[2023,5,12]],"date-time":"2023-05-12T06:12:09Z","timestamp":1683871929000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Cell-autonomous and differential endocannabinoid signaling impacts the development of presynaptic retinal ganglion cell axon connectivity in vivo"],"prefix":"10.3389","volume":"15","author":[{"suffix":"Jr.","given":"Rodrigo","family":"Del Rio","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosa G.","family":"Serrano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Gomez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joshua C.","family":"Martinez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina A.","family":"Edward","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rommel A.","family":"Santos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth S.","family":"Diaz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susana","family":"Cohen-Cory","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2023,5,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7284","DOI":"10.1007\/s12035-019-1603-5","article-title":"The endocannabinoid system is present in rod outer segments from retina and is modulated by light.","volume":"56","author":"Aguirre","year":"2019","journal-title":"Mol. 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