Jason Tait Sanchez, Ph.D., CCC-A, FAAA, Associate Professor at Northwestern University, discusses resurgent sodium current in the nervous system
Hui Hong, Ph.D. i* and Jason Tait Sanchez. i,ii,iii
iThe Roxelyn and Richard Pepper Department of Communication Sciences and Disorders, iiNeurobiology Department and iiiThe Hugh Knowles Hearing Research Center. Northwestern University. Evanston, Illinois, 60208, U.S.
*Current affiliation: Oregon Hearing Research Center, Oregon Health and Science University. Portland, Oregon, 97239, U.S.
Hui Hong, Ph.D., is a postdoctoral research fellow at the Oregon Health and Science University.
Jason Tait Sanchez, Ph.D., CCC-A, FAAA, is an Associate Professor at Northwestern University.
The nervous system plays a pivotal role in sensory and motor functions of all vertebrates. Fundamental to these functions is sophisticated brain signal processing. For a variety of neurons, the ability to fire rapid action potentials (APs) in a repetitive manner is required for normal function. To promote rapid and repetitive AP firing, numerous synaptic and intrinsic specialisations work synergistically, an important one of which is resurgent current (INaR) of voltage-dependent sodium (NaV) channels 1. INaR is a small sodium current that occurs immediately after the generation of an AP.
First identified in cerebellar Purkinje neurons, INaR has also been observed in both peripheral and central neurons, such as spinal sensory neurons, spiral ganglion neurons and their central targets 2-6. Recently, work from the Central Auditory Physiology Laboratory at Northwestern University reported it in the auditory system of non-mammalian neurons (i.e., chickens), suggesting a conserved phenotype across species 7-9. In this research profile, we discuss the general properties of INaR in the brain and highlight its importance in the auditory system.
Functional properties and molecular substrates of INaR
INaR supports rapid and repetitive AP firing of neurons 5,7,10-12. It reduces the inactivation of NaV channels while producing a small depolarising drive to the neuronal membrane 2,13-15. This function of INaR is rooted in the specialised molecular structure of NaV channels, comprising of the α-subunits and the auxiliary β-subunits 1. In terms of α-subunits, NaV1.6 was first identified to carry INaR due to its extensive expression in the brain 16. However, other types of α-subunit, including NaV1.2, 1.5 and 1.7, are also capable of mediating INaR 17,18. Genetic mutations in some NaV channel subtypes (e.g., NaV1.4) can increase or trigger the generation of INaR, suggesting a potential link between INaR and certain pathologies 18. Taken together, multiple α-subunits are substrates for INaR.
The generation of INaR depends on not only the α-subunits, but more importantly, the accessory β-subunits. β4-subunits have been proposed to form the “open channel blocker” that induce INaR 19-21, although this has recently been challenged 22. Nevertheless, the underlying amino acid sequence of the β4-subunit is also conserved across species 23. Upon depolarisation that opens NaV channels, the open channel blocker occupies the inner pore region of the nearby α-subunit. During repolarisation, the blocker loses its affinity to the pore, resulting in a brief period of the pore to be in an open state. This is when INaR is observed 1. The process to generate INaR is competitive, because the classic inactivation gate of NaV channels (i.e., the cytoplasmic linker between the III and IV domains of the α-subunit) also tends to occupy the pore 14. As a result of this competition, the activation of the open channel blocker can reduce the inactivation of NaV channels, facilitate their recovery after depolarisation and eventually promote rapid AP firing for neurons 7,8,10,24.
INaR in the auditory system
In order to perform rapid auditory tasks, neurons in the auditory system show remarkable ability to fire APs at high rates 25-28. Not surprisingly, INaR has been reported in several auditory structures, including spiral ganglion neurons, neurons in the medial nucleus of the trapezoid body (MNTB) and nucleus magnocellularis (NM) – the avian analogue of the mammalian cochlear nucleus 4-7. Recent studies on INaR in auditory neurons have provided profound insights into its function, development, topography and association with pathologies.
INaR increases neuronal excitability and helps enable AP firing at high rates in spiral ganglion neurons 4. This function ensures fast and precise signal transmission between the peripheral inner ear (i.e., the cochlea) and the central auditory brainstem. In the central auditory brainstem, INaR also has several aspects of functional significance. First, INaR plays an important role in regulating high-frequency firing in NM and MNTB neurons 6,7. A model NM neuron with no INaR failed to follow high-frequency inputs with good fidelity. Second, in the calyx of Held – a specific axonal terminal in the MNTB – INaR contributes to the generation of depolarising afterpotential that is essential for high-frequency firing 5. As a result, INaR helps promote reliable synaptic transmission between neurons.
Weak INaR is present in auditory neurons during a prehearing period with its strength increasing with age 4,7. Interestingly, it is not until the onset of hearing when a drastic increase in INaR amplitude is observed. This applies both to precocious animals (e.g., chickens) with their hearing onset occurring in ovo and to mammals (e.g., mice and rats) that develop hearing postnatally. These observations further support the idea that INaR is evolutionarily conserved. Mature auditory neurons exhibit robust expression of NaV1.6 and β4-subunits 4,29. However, evidence from NM neurons suggests different α-subunits may mediate INaR during development 7. Yet, thorough documentation of molecular substrates of INaR during auditory development is lacking.
The development of INaR displays a topographical and tonotopic pattern as well. INaR first appears and exhibits larger amplitude in high-frequency spiral ganglion neurons that innervate the basal turn of the cochlea. However, this tonotopic gradient is lost when entering adulthood 4. In NM neurons, the high-frequency region also shows larger INaR than lower-frequency neurons and this gradient is maintained with maturation 8.
INaR is associated with several pathological conditions. First, in MNTB neurons of deaf mice, INaR is present with slower kinetics compared to normal hearing mice, likely being a compensation mechanism to promote excitability with weak inputs. Interestingly, when normal neurons were incorporated with “deaf” INaR, its ability to fire APs at high rates improved 6. Second, INaR is significantly reduced with myelin degeneration. Accompanying this deficit is the structural relocation of NaV1.6 and the absence of β4-subunits in the calyx of Held 29. These observations suggest a disruption of synaptic transmission in the MNTB.
Summary
INaR is an important and evolutionarily conserved factor underlying the fast and precise signal processing in the nervous system. The deficits of INaR are related to many pathologies. Nevertheless, aspects regarding the functional significance, molecular substrates, development, topographical distribution and channelopathies of INaR are still largely unexplored.
The references for this article can be found at: https://caplab.northwestern.edu/
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