Pharmacological modulation of Kv3.1 mitigates auditory midbrain temporal processing deficits following auditory nerve damage
Chambers, Anna R.
Large, Charles H.
Kaczmarek, Leonard K.
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CitationChambers, Anna R., Nadia Pilati, Pooja Balaram, Charles H. Large, Leonard K. Kaczmarek, and Daniel B. Polley. 2017. “Pharmacological modulation of Kv3.1 mitigates auditory midbrain temporal processing deficits following auditory nerve damage.” Scientific Reports 7 (1): 17496. doi:10.1038/s41598-017-17406-x. http://dx.doi.org/10.1038/s41598-017-17406-x.
AbstractHigher 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.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:34651844
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