Resurgent sodium current promotes action potential firing in the avian auditory brainstem

Abstract

Key points Auditory brainstem neurons of all vertebrates fire phase‐locked action potentials (APs) at high rates with remarkable fidelity, a process controlled by specialized anatomical and biophysical properties.This is especially true in the avian nucleus magnocellularis (NM) – the analogue of the mammalian anteroventral cochlear nucleus.In addition to high voltage‐activated potassium (KHVA) channels, we report, using whole cell physiology and modelling, that resurgent sodium current (I NaR) of sodium channels (NaV) is equally important and operates synergistically with KHVA channels to enable rapid AP firing in NM.Anatomically, we detected strong NaV1.6 expression near hearing maturation, which was less distinct during hearing development despite functional evidence of I NaR, suggesting that multiple NaV channel subtypes may contribute to I NaR.We conclude that I NaR plays an important role in regulating rapid AP firing for NM neurons, a property that may be evolutionarily conserved for functions related to similar avian and mammalian hearing. AbstractAuditory brainstem neurons are functionally primed to fire action potentials (APs) at markedly high rates in order to rapidly encode the acoustic information of sound. This specialization is critical for survival and the comprehension of behaviourally relevant communication functions, including sound localization and distinguishing speech from noise. Here, we investigated underlying ion channel mechanisms essential for high‐rate AP firing in neurons of the chicken nucleus magnocellularis (NM) – the avian analogue of bushy cells of the mammalian anteroventral cochlear nucleus. In addition to the established function of high voltage‐activated potassium channels, we found that resurgent sodium current (I NaR) plays a role in regulating rapid firing activity of late‐developing (embryonic (E) days 19–21) NM neurons. I NaR of late‐developing NM neurons showed similar properties to mammalian neurons in that its unique mechanism of an ‘open channel block state’ facilitated the recovery and increased the availability of sodium (NaV) channels after depolarization. Using a computational model of NM neurons, we demonstrated that removal of I NaR reduced high‐rate AP firing. We found weak I NaR during a prehearing period (E11–12), which transformed to resemble late‐developing I NaR properties around hearing onset (E14–16). Anatomically, we detected strong NaV1.6 expression near maturation, which became increasingly less distinct at hearing onset and prehearing periods, suggesting that multiple NaV channel subtypes may contribute to I NaR during development. We conclude that I NaR plays an important role in regulating rapid AP firing for NM neurons, a property that may be evolutionarily conserved for functions related to similar avian and mammalian hearing.

Persistent sodium current blockers can suppress seizures caused by loss of low‐threshold D‐type potassium currents: Predictions from an in silico study of Kv1 channel disorders

“…Resurgent currents appear when neurons are repolarized after prolonged depolarization. They are reported to promote spontaneous firing and high‐frequency firing of inhibitory neurons and may be a promising antiepileptic therapeutic target . A computer model that includes the unique activation features of resurgent currents is still to be developed.…”

Diverse Intrinsic Properties Shape Functional Phenotype of Low-Frequency Neurons in the Auditory Brainstem

“…Simulation of NMc electrical activity were performed in NEURON 7.1 ( Hines and Carnevale, 1997 ) by employing a single-compartment model ( Table 2 ). The NMc model was based on our NM model previously described and all ion currents were modeled using the same formalism ( Tables 2 , 3 , Hong et al, 2017 ; Lu et al, 2017 ). Briefly, this model contains currents mediated by low- and high-voltage activated potassium (K + LV A and K + HV A , respectively) channels, Na V , and passive leak channels.…”

“… Kuba and Ohmori (2009) also showed larger Na V current amplitude and higher Na V channel density, as indicated by stronger immunoreactivity, toward lower-frequency NM. Furthermore, we showed that Na V 1.6-channel subtype is expressed in mid- to high-frequency NM and carry robust resurgent Na V current ( I NaR ) ( Hong et al, 2017 ). I NaR is a prevalent property conserved in auditory structures of both avians and mammals and plays an important role in high-frequency AP firing of peripheral and brainstem neurons ( Leao K.E.…”

“…I NaR is a prevalent property conserved in auditory structures of both avians and mammals and plays an important role in high-frequency AP firing of peripheral and brainstem neurons ( Leao K.E. et al, 2006 ; Kim et al, 2010 ; Browne et al, 2017 ; Hong et al, 2017 ). It remains to be determined if NMc neurons have different Na V channel properties compared to mid- to high-frequency neurons and to what extent – if any – I NaR present with tonotopic heterogeneity that contributes to the distinct AP firing pattern of NMc neurons.…”

“…The current study addresses these issues by characterizing the underlying K V and Na V channel properties that contribute to the functional phenotype of NMc neurons and is a follow-up to our first report regarding these neurons ( Wang et al, 2017 ). To ensure fair comparisons across tonotopic regions of NM, we applied similar methods of electrophysiology, immunocytochemistry and computational modeling we previously reported ( Hong et al, 2016 , 2017 ). We found that NMc neurons burst fired at relatively fast rates to low-frequency sinusoidal current injections that was partially attributed to reduced K V 1 and K V 3 currents but higher K V 2 currents – properties that differ from higher-frequency neurons ( Hong et al, 2016 ).…”