{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T15:07:36Z","timestamp":1784905656106,"version":"3.55.0"},"reference-count":67,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T00:00:00Z","timestamp":1713312000000},"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. Cell. Neurosci."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Cochlear afferent synapses connecting inner hair cells to spiral ganglion neurons are susceptible to excitotoxic trauma on exposure to loud sound, resulting in a noise-induced cochlear synaptopathy (NICS). Here we assessed the ability of cyclic AMP-dependent protein kinase (PKA) signaling to promote cochlear synapse regeneration, inferred from its ability to promote axon regeneration in axotomized CNS neurons, another system refractory to regeneration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We mimicked NICS <jats:italic>in vitro<\/jats:italic> by applying a glutamate receptor agonist, kainic acid (KA) to organotypic cochlear explant cultures and experimentally manipulated cAMP signaling to determine whether PKA could promote synapse regeneration. We then delivered the cAMP phosphodiesterase inhibitor rolipram via implanted subcutaneous minipumps in noise-exposed CBA\/CaJ mice to test the hypothesis that cAMP signaling could promote cochlear synapse regeneration <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We showed that the application of the cell membrane-permeable cAMP agonist 8-cpt-cAMP or the cAMP phosphodiesterase inhibitor rolipram promotes significant regeneration of synapses <jats:italic>in vitro<\/jats:italic> within twelve hours after their destruction by KA. This is independent of neurotrophin-3, which also promotes synapse regeneration. Moreover, of the two independent signaling effectors activated by cAMP \u2013 the cAMP Exchange Protein Activated by cAMP and the cAMP-dependent protein kinase \u2013 it is the latter that mediates synapse regeneration. Finally, we showed that systemic delivery of rolipram promotes synapse regeneration <jats:italic>in vivo<\/jats:italic> following NICS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p><jats:italic>In vitro<\/jats:italic> experiments show that cAMP signaling promotes synapse regeneration after excitotoxic destruction of cochlear synapses and does so via PKA signaling. The cAMP phosphodiesterase inhibitor rolipram promotes synapse regeneration <jats:italic>in vivo<\/jats:italic> in noise-exposed mice. Systemic administration of rolipram or similar compounds appears to provide a minimally invasive therapeutic approach to reversing synaptopathy post-noise.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fncel.2024.1363219","type":"journal-article","created":{"date-parts":[[2024,4,17]],"date-time":"2024-04-17T04:42:51Z","timestamp":1713328971000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Cyclic AMP signaling promotes regeneration of cochlear synapses after excitotoxic or noise trauma"],"prefix":"10.3389","volume":"18","author":[{"given":"Sriram","family":"Hemachandran","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine J.","family":"Kane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven H.","family":"Green","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,4,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.neuropharm.2008.04.005","article-title":"cAMP promotes neurite outgrowth and extension through protein kinase A but independently of Erk activation in cultured rat motoneurons.","volume":"55","author":"Aglah","year":"2008","journal-title":"Neuropharmacology"},{"key":"B2","doi-asserted-by":"publisher","first-page":"13110","DOI":"10.1523\/JNEUROSCI.1014-14.2014","article-title":"Postnatal expression of neurotrophic factors accessible to spiral ganglion neurons in the auditory system of adult hearing and deafened rats.","volume":"34","author":"Bailey","year":"2014","journal-title":"J. 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