Demyelination in the central nervous system, resulting from genetic mutations or autoimmune disease (e.g. multiple sclerosis, MS), causes hearing impairments such as sudden hearing loss, inability to localize sound and/or tinnitus. Such deficits are generally attributed to the decrements in conduction velocity and temporal fidelity that accompany axon demyelination. However, the direct impact of demyelination on synapse functional parameters, including presynaptic excitability, neurotransmitter release and synaptic plasticity, is largely unknown in the auditory nervous system. To what extent do deficits in synapse function associated with demyelination contribute to hearing impairments? The objective of this proposal is to investigate the role of myelin ensheathment on the functional and structural maturation of the calyx of Held synapse in the auditory pathway. Our published and preliminary studies show that the loss of condensed myelination increases timing errors and failures in synaptic transmission at the calyx synapses in the auditory brainstem. Changes at the level of individual synapses are associated with delayed and degraded signal transmission along the auditory pathway in an in vivo auditory brainstem response test in myelin-deficient rats. Based on the preliminary data, we hypothesize that axon myelination is required for the proper location of ion channels at hemi-nodes and presynaptic terminals, for precision of transmitter release involved in short-term plasticity and for development of a tight synaptic structure. To test this hypothesis, we will use the Long-Evans Shaker rat, which completely lacks central myelination, excluding confounding effects associated with inflammatory factors. We will perform patch-clamp recordings of presynaptic terminals, post-synaptic neurons and astrocytes, along with Na+ and Ca2+ imaging.
In Aim 1, we will test the hypothesis that lack of myelination disrupts the expression pattern of Na+ and K+ channels and leads to impulse timing errors and failures at presynaptic terminals.
In Aim 2, we will test the hypothesis that lack of myelination decreases synaptic efficacy by increasing presynaptic Ca2+ accumulation and causing asynchrony of synaptic signals.
In Aim 3, we will test the hypothesis that lack of myelin spatiotemporally disrupts synapse-astrocyte communication and leads to excessive glutamate-mediated axonal and synaptic degeneration. These studies will have a significant impact on our understanding of damaged auditory processing following central demyelination, and contribute to improve treatment of hearing disorders in MS and auditory neuropathy. Furthermore, an improved understanding the consequences of central demyelination at the synaptic level will have broad relevance for the entire field of neurodegenerative diseases.

Public Health Relevance

Demyelination in the central nervous system, resulting from genetic mutations or autoimmune disease (e.g. multiple sclerosis, MS), causes hearing impairments such as sudden hearing loss, inability to localize sound and/or tinnitus (ringing in the ears). The goal of this study is to determine the underlying mechanisms whereby lack of myelination impacts auditory transmission at the synaptic level. The results will lead to new strategies for prevention, rehabilitation and remediation of hearing disorders in patients with MS and auditory neuropathy.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
1R01DC013157-01A1
Application #
8697308
Study Section
Auditory System Study Section (AUD)
Program Officer
Cyr, Janet
Project Start
2014-03-10
Project End
2019-02-28
Budget Start
2014-03-10
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$315,163
Indirect Cost
$102,663
Name
University of Texas Health Science Center San Antonio
Department
Physiology
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
Berret, Emmanuelle; Kim, Sei Eun; Lee, Seul Yi et al. (2016) Functional and structural properties of ion channels at the nerve terminal depends on compact myelin. J Physiol 594:5593-609
Xu, Jie; Berret, Emmanuelle; Kim, Jun Hee (2016) Activity-Dependent Formation and Location of Voltage-Gated Sodium Channel Clusters at a CNS Nerve Terminal during Postnatal Development. J Neurophysiol :jn.00617.2016
Kim, Sei Eun; Lee, Seul Yi; Blanco, Cynthia L et al. (2014) Developmental profiles of the intrinsic properties and synaptic function of auditory neurons in preterm and term baboon neonates. J Neurosci 34:11399-404