Moderate exposure to noise can cause damage to the synapses between inner hair cells (IHCs) and type I spiral ganglion neurons (SGNs) of the cochlea. This “synaptopathy” due to noise is a consequence of glutamate excitotoxicity and resultant Ca2+-influx into the synaptic bouton, largely mediated by Ca2+-permeable AMPA receptors (CP-AMPARs). This trauma can be mimicked in vitro using organotypic cochlear explant cultures by exposing them to glutamate receptor agonists. Once lost, these synapses do not normally regenerate, but the exogenous application of neurotrophic factors promotes their regeneration. The work described in my thesis takes advantage of the cochlear explant system to investigate pharmacological approaches to the protection of synapses during excitotoxic trauma, and their regeneration after the insults have caused synaptopathy. Chapter 2 describes work that led to the discovery of the efficacy of IEM-1460, a selective CP-AMPAR blocker, in protecting synapses from damage during excitotoxic trauma. Chapter 3 describes a novel role for CNTF, a neurotrophic factor expressed in the cochlea, in promoting the regeneration of synapses after their loss. In chapter 4 I show the ability of progesterone, a female steroid sex hormone, in promoting synapse regeneration after synaptopathy, and explore the underlying biological mechanism through which it exerts these effects by interrogating various neuronal intracellular signaling pathways through which it may be working. These findings provide promising insights into potential routes for the development of pharmacological therapies that can be harnessed for use in humans with noise-damaged ears.
|Advisor:||Green, Steven H.|
|Commitee:||Lee, Amy, Eberl, Daniel, Dailey, Michael E., Hansen, Marlan|
|School:||The University of Iowa|
|School Location:||United States -- Iowa|
|Source:||DAI-B 82/1(E), Dissertation Abstracts International|
|Keywords:||Cochlea, Regeneration, SGN, Synapse, Synaptopathy|
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