Pharmacological modulation of Kv3.1 mitigates auditory midbrain temporal processing deficits following auditory nerve damage

Higher stages of central auditory processing compensate for a loss of cochlear nerve synapses by increasing the gain on remaining afferent inputs, thereby restoring firing rate codes for rudimentary sound features. The benefits of this compensatory plasticity are limited, as the recovery of precise...

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Veröffentlicht in:Scientific reports Jg. 7; H. 1; S. 17496 - 15
Hauptverfasser: Chambers, Anna R., Pilati, Nadia, Balaram, Pooja, Large, Charles H., Kaczmarek, Leonard K., Polley, Daniel B.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 13.12.2017
Nature Publishing Group
Schlagworte:
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Action potential
Action Potentials - drug effects
Aging
Animals
Auditory nerve
Auditory Pathways - drug effects
Auditory Pathways - injuries
Auditory Pathways - metabolism
Auditory Perception - drug effects
Auditory Perception - physiology
Auditory plasticity
Brain stem
Cochlea
Cochlear Nerve - injuries
Cochlear Nerve - metabolism
Compulsive Behavior
Cortex (auditory)
Disease Models, Animal
Firing pattern
Hair
Humanities and Social Sciences
Imidazoles - pharmacology
Inferior colliculus
Information processing
Membrane Transport Modulators - pharmacology
Mesencephalon
Mesencephalon - drug effects
Mesencephalon - metabolism
Mice
Models, Biological
multidisciplinary
Neural coding
Neurons
Neurons - drug effects
Neurons - metabolism
Noise
Ototoxicity
Ouabain
Potassium
Potassium channels
Potassium channels (voltage-gated)
Pyrimidines - pharmacology
Recovery of Function - drug effects
Science
Science (multidisciplinary)
Sensory neurons
Shaw Potassium Channels - metabolism
Sound
Synapses
Synchronization
Temporal lobe
Temporal variations
Tinnitus
Tissue Culture Techniques
Vestibulocochlear Nerve Diseases - drug therapy
Vestibulocochlear Nerve Diseases - metabolism
ISSN:2045-2322, 2045-2322
Online-Zugang:Volltext
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Zusammenfassung:Higher stages of central auditory processing compensate for a loss of cochlear nerve synapses by increasing the gain on remaining afferent inputs, thereby restoring firing rate codes for rudimentary sound features. The benefits of this compensatory plasticity are limited, as the recovery of precise temporal coding is comparatively modest. We reasoned that persistent temporal coding deficits could be ameliorated through modulation of voltage-gated potassium (Kv) channels that regulate temporal firing patterns. Here, we characterize AUT00063, a pharmacological compound that modulates Kv3.1, a high-threshold channel expressed in fast-spiking neurons throughout the central auditory pathway. Patch clamp recordings from auditory brainstem neurons and in silico modeling revealed that application of AUT00063 reduced action potential timing variability and improved temporal coding precision. Systemic injections of AUT00063 in vivo improved auditory synchronization and supported more accurate decoding of temporal sound features in the inferior colliculus and auditory cortex in adult mice with a near-complete loss of auditory nerve afferent synapses in the contralateral ear. These findings suggest modulating Kv3.1 in central neurons could be a promising therapeutic approach to mitigate temporal processing deficits that commonly accompany aging, tinnitus, ototoxic drug exposure or noise damage.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-017-17406-x