Thesis
Investigating synapse regeneration: transcriptional mechanisms and temporal constraints
University of Iowa
Master of Science (MS), University of Iowa
Autumn 2025
Abstract
Cochlear synapses between inner hair cells and spiral ganglion neurons facilitate transmission of auditory information from the periphery to the brainstem. These synapses are susceptible to damage caused by noise, aging, or ototoxic drugs, which can lead to hearing deficits. Spontaneous synapse regeneration in the cochlea is self-limited but may be induced with neurotrophic factors, although these large biomolecules require invasive delivery methods that are not practical for clinical use. Therefore, systemically deliverable small molecules that promote synapse regeneration provide a more viable therapeutic approach. We have identified the cAMP-PKA signaling pathway as a promising target capable of promoting cochlear synapse regeneration via small-molecule activation. Here, we investigate the efficacy and transcription-dependency of cAMP-induced synapse regeneration with treatment of cell-permeable cAMP analog 8-CPT-cAMP and transcription inhibitor actinomycin D for 16 hours in organotypic cochlear explant cultures. We found that the efficacy of 8-CPT-cAMP in promoting synapse regeneration in 16 hours was comparable to 72-hour treatment. Furthermore, inhibition of transcription does not block cAMP-induced synapse regeneration, demonstrating that synapse regeneration is largely transcription-independent.
Rolipram, a small-molecule PDE4 inhibitor that prevents cAMP breakdown and thereby elevates intracellular cAMP, has been shown to promote synapse regeneration and partial recovery of ABR wave-I amplitude in noise-exposed mice when administered one day after noise exposure. Establishing a therapeutic window for rolipram is critical to determining effectiveness of delayed treatment, which could enhance its potential for future clinical use in humans. Here, we ask how long the capacity for synapse regeneration persists following noise exposure. We systemically delivered rolipram either two or three days after noise exposure to determine whether delayed administration of rolipram promotes synapse regeneration. Measurements of auditory brainstem response (ABR) wave-I amplitude were taken before and after noise exposure and synapses were quantified in histological preparations. We found that rolipram promotes regional synapse regeneration and partial ABR wave-I amplitude recovery when administered within two days post-noise, but not after three days. These findings identify a limited therapeutic window for rolipram (1-2 days post-noise exposure) and reinforce the need for early pharmacological activation of cAMP-PKA signaling to promote cochlear synapse regeneration and prevent permanent synapse loss after noise exposure.
Details
- Title: Subtitle
- Investigating synapse regeneration: transcriptional mechanisms and temporal constraints
- Creators
- Kieran Coffey
- Contributors
- Steven H Green (Advisor)Shawn Goodman (Committee Member)Dan Eberl (Committee Member)
- Resource Type
- Thesis
- Degree Awarded
- Master of Science (MS), University of Iowa
- Degree in
- Biology
- Date degree season
- Autumn 2025
- Publisher
- University of Iowa
- Number of pages
- x, 46 pages
- Copyright
- Copyright 2025 Kieran Coffey
- Language
- English
- Date submitted
- 12/03/2025
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (page 42-46).
- Public Abstract (ETD)
Many people with normal hearing still struggle to follow conversations in noisy places, such as a bar. One reason is damage to the tiny connections that pass sound signals from the inner ear to the brain. Right now, there are no non-invasive medicines that can repair these connections after noise damage.
My research tested whether boosting a natural growth signal inside neurons can rebuild these connections. In inner-ear tissue, boosting this signal repaired connections more quickly than previously known and without switching on new genes. In mice exposed to moderate noise, I found that a drug that boosts the same growth signal repaired more inner-ear connections and strengthened the ear-to-brain electrical response compared with untreated mice, but only when given within two days after noise exposure. After three days, it no longer helped.
These findings reveal a short time window, about one to two days after noise exposure, when medicine could help repair. They point toward future treatments that aim to restore clarity, not just volume, for people with hearing difficulties.
- Academic Unit
- Biology
- Record Identifier
- 9985135247302771
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