Cyclic AMP signaling promotes regeneration of cochlear synapses after excitotoxic or noise trauma

Sriram Hemachandran; Ning Hu; Catherine Kane; Steven Green

doi:10.3389/fncel.2024.1363219

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Cyclic AMP signaling promotes regeneration of cochlear synapses after excitotoxic or noise trauma

Journal article

Open access

Peer reviewed

Cyclic AMP signaling promotes regeneration of cochlear synapses after excitotoxic or noise trauma

Sriram Hemachandran, Ning Hu, Catherine Kane and Steven Green

Frontiers in cellular neuroscience, Vol.18, 1363219

04/17/2024

DOI: 10.3389/fncel.2024.1363219

PMCID: PMC11061447

PMID: 38694536

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https://doi.org/10.3389/fncel.2024.1363219View

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Abstract

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). We mimicked this trauma in an in vitro model by applying a glutamate receptor agonist, kainic acid (KA) to organotypic cochlear . Regeneration of the lost synapses is very limited but, we show here, can be promoted by cAMP signaling in the in vitro model and in noise-exposed mice. Indeed, using the in vitro model, we show that the application of the cell membrane-permeable cAMP agonist 8-cpt-cAMP or the cAMP phosphodiesterase inhibitor rolipram promotes significant regeneration of synapses within twelve hours after their destruction by KA. This is independent of neurotrophin-3, which also promotes synapse regeneration. Two independent signaling effectors are activated by cAMP: the cAMP Exchange Protein Activated by cAMP and the cAMPdependent protein kinase. We show here that it is the latter that mediates synapse regeneration. Finally, we show that systemic delivery of rolipram from a subcutaneously implanted minipump in adult mice promotes synapse regeneration in vivo following NICS.Thus, systemic administration of rolipram or similar compounds may provide a minimally invasive therapeutic approach to reversing synaptopathy post-noise.

Trauma

Agonists

Cell membranes

Cochlea

Cyclic AMP

Excitotoxicity

Glutamic acid receptors

Hair

Hair cells

Hearing protection

Kainic acid

Kinases

Neurotrophin 3

Phosphodiesterase inhibitors

Regeneration

Rolipram

Sensory neurons

Spiral ganglion

Details

Title: Subtitle: Cyclic AMP signaling promotes regeneration of cochlear synapses after excitotoxic or noise trauma
Creators: Sriram Hemachandran
Ning Hu
Catherine Kane
Steven Green
Resource Type: Journal article
Publication Details: Frontiers in cellular neuroscience, Vol.18, 1363219
Publisher: Frontiers Research Foundation
DOI: 10.3389/fncel.2024.1363219
PMID: 38694536
PMCID: PMC11061447
ISSN: 1662-5102
Language: English
Date published: 04/17/2024
Academic Unit: Biology; Otolaryngology
Record Identifier: 9984617005502771

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