The local translation of KNa in dendritic projections of auditory neurons and the roles of KNa in the transition from hidden to overt hearing loss

Abstract

Local and privileged expression of dendritic proteins allows segregation of distinct functions in a single neuron but may represent one of the underlying mechanisms for early and insidious presentation of sensory neuropathy. Tangible characteristics of early hearing loss (HL) are defined in correlation with nascent hidden hearing loss (HHL) in humans and animal models. Despite the plethora of causes of HL, only two prevailing mechanisms for HHL have been identified, and in both cases, common structural deficits are implicated in inner hair cell synapses, and demyelination of the auditory nerve (AN). We uncovered that Na+-activated K+ (KNa) mRNA and channel proteins are distinctly and locally expressed in dendritic projections of primary ANs and genetic deletion of KNa channels (Kcnt1 and Kcnt2) results in the loss of proper AN synaptic function, characterized as HHL, without structural synaptic alterations. We further demonstrate that the local functional synaptic alterations transition from HHL to increased hearing-threshold, which entails changes in global Ca2+ homeostasis, activation of caspases 3/9, impaired regulation of inositol triphosphate receptor 1 (IP3R1), and apoptosis-mediated neurodegeneration. Thus, the present study demonstrates how local synaptic dysfunction results in an apparent latent pathological phenotype (HHL) and, if undetected, can lead to overt HL. It also highlights, for the first time, that HHL can precede structural synaptic dysfunction and AN demyelination. The stepwise cellular mechanisms from HHL to canonical HL are revealed, providing a platform for intervention to prevent lasting and irreversible age-related hearing loss (ARHL).

Guanylyl Cyclase A/cGMP Signaling Slows Hidden, Age- and Acoustic Trauma-Induced Hearing Loss

“…In conclusion, this finding reveals a clear role for GC-A ligands in maintaining basic IHC synapse function and pre-and postsynaptic integrity of IHC in high-frequency cochlear regions during aging and AT. The metabolic sensitivity of IHC synapses and their contribution to hidden and age-dependent hearing loss is thereby confirmed (Keithley, 2019;Lee et al, 2019). This also confirms our initial hypothesis that GC-A ligands act as possible key regulators of energy consumption and metabolism to maintain hearing function.…”

Sodium sensitivity of KNachannels in mouse CA1 neurons

“…This suggests the intriguing possibility that K Na channels may play a more prominent role in the dendrites relative to the soma. Indeed, K Na mRNA and protein is found in the dendrites of auditory neurons (28), and overlapping and nonoverlapping expression of Slick and Slack have been described in various cell types and regions in rat brain (29). Some cell types have been shown to have a large component of K þ current in response to Na þ entry.…”

Prestin amplifies cardiac motor functions

“…Single-molecule fluorescence in situ hybridization (smFISH) SmFISH was performed as previously described (Lee et al, 2019;Perkins et al, 2020) in single isolated ventricular myocytes from WT and Slc26a5 À/À mice using probes developed for Slc26a5 and Slc26a6. Probe hybridization closely followed the manufacturer's instructions (Advanced Cell Diagnostics, Newark, CA, U.S.A.).…”