Abstract
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.
Highlights
Cochlear frequency processing can be conceptualized as a limited-resolution ‘filter bank’ that decomposes broadband sounds into a spatially organized array of narrowband signals
Severe cochlear neuropathy was induced in adult CBA/CaJ mice with unilateral round window applications of ouabain, a Na+/K+ ATPase pump inhibitor that has been shown to selectively eliminate Type-I spiral ganglion neurons (SGNs) without damaging sensory and non-sensory cells in the cochlea[32,33]
Histological analysis and cochlear function testing reveal that application of ouabain to the cochlear round window eliminated over 95% of Type I spiral ganglion afferent synapses (as assessed by synaptic counts between hair cells and Type I SGNs, n = 349 inner hair cells in ouabain-treated and 372 inner hair cells in control ears, F(1) = 345.7, p < 0.01, repeated-measures ANOVA, Fig. 1a) without damaging cochlear hair cells, as inferred from normal distortion product otoacoustic emission (DPOAE) thresholds between the treated and untreated ear (F(1) = 1.36, p = 0.27, repeated-measures ANOVA, Fig. 1b)
Summary
Cochlear frequency processing can be conceptualized as a limited-resolution ‘filter bank’ that decomposes broadband sounds into a spatially organized array of narrowband signals. At the level of the auditory cortex (ACtx), neural circuits compensate for cochlear afferent loss by decreasing local inhibitory tone and increasing the central gain on diminished afferent signals[11,12,13,14,15]. This compensatory plasticity restores higher auditory coding and perceptual awareness of basic auditory features that can be encoded by variations in overall firing rate, but offers comparatively little benefit for the fine-grained temporal analysis that is uniquely performed by specialized auditory brainstem and midbrain circuits[11,12]. After determining that the central auditory pathway of denervated mice express high levels of Kv3.1, we return to the intact preparation and ask whether systemic administration of AUT00063 can rapidly improve temporal coding fidelity in the IC of awake mice as well as downstream auditory areas
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