Interactions among Diameter, Myelination and the Na/K pump Affect Axonal Resilience to High Frequency Spiking

Abstract

Axons reliably conduct action potentials between neurons and/or other targets. Axons have widely variable diameters and can be myelinated or unmyelinated. Although the effect of these factors on propagation speed is well studied, how they constrain axonal resilience to high frequency spiking is incompletely understood. Maximal firing frequencies range from ~ 1 Hz to > 300 Hz across neurons, but the process by which Na/K pumps counteract Na+ influx is slow, and it is unclear the extent to which slow Na+ removal is compatible with high frequency spiking. Modeling the process of Na+ removal in unmyelinated and myelinated axons shows that both increasing diameter and myelination slow down [Na+] accumulation and increase axonal resilience to high frequency spiking. Increasing pump density alleviates [Na+] accumulation, but can paradoxically reduce the resilience. We speculate that [Na+] accumulation may contribute to fatigue after continuous high frequency firing.

Resilience of compound action potential peaks to high‐frequency firing in the mouse optic nerve

“…Constitutively open astrocytic Kir4.1 channels (3) and the NKA (4) buffer the elevated interstitial K + , which causes electrotonic repulsion of K + from distant astrocytes in the syncytium (5), an example of spatial buffering (MacAulay, 2020). The stimulus induced elevation in nodal Na + is predicted to spread laterally (6) to (juxta)paranodal regions (Zang & Marder, 2021). Mitochondria in these regions are sensitive to elevated Na + and can move towards the nodes (7) to facilitate the axonal NKA in restoring baseline [Na + ] ( Ohno et al, 2011).…”

“…The decline in amplitude denotes the frequency above which the energy demand created by the stimulus exceeds the energy supply. Modeling studies suggest nodal Na + influx as the prime contributing factor in CAP attenuation (Perge et al, 2009;Zang & Marder, 2021). In MON, both experimental and computational studies find small axons fire at 5 Hz whereas large axons fire at 30 Hz, suggesting the principal determinant governing an axon's ability to fire at high frequency is its size (Perge et al, 2009(Perge et al, , 2012.…”

“…Supporting evidence comes from sciatic nerve studies where the A peak, produced by large myelinated axons up to 15 μm in diameter (Rich & Brown, 2018), can conduct at stimulus frequencies of 100 Hz (Rich et al, 2022). The proposed decline in the small axon conduction during high-frequency firing predicted from modeling studies (Zang & Marder, 2021) has recently been challenged. The model used Ohm's law to describe I Na , which led to loss of small axon conduction.…”

“…A considerable volume (30%) of the MON is occupied by astrocytes (Perge et al, 2009), which efficiently buffer interstitial K + via the energy dependent Na + K + ATPase (NKA) and Kir4.1 channels, such that [K + ] o is maintained below a ceiling level (Ransom et al, 2000), allowing fidelity of sustained action potential conduction. Computational studies based on surface area to volume relationships of nodal Na + channel density, NKA expression and axoplasmic mitochondrial density proposed intra-axonal accumulation of Na + as a likely cause of action potential decrease at high firing frequencies, with smaller axons more susceptible than large axons (Perge et al, 2009;Zang & Marder, 2021).…”

Acute Axon Damage and Demyelination are Mitigated by 4-Aminopyridine (4-AP) Therapy after Experimental Traumatic Brain Injury

“…This initial study focused on white matter injury, specifically CC axon and myelin pathology, whereas 4-AP effects may also involve glial cells or peripheral immune cells (Dietrich et al, 2021). Broader 4-AP effects may involve neural circuit and synaptic properties, and the fidelity of high frequency signal transmission (Yang et al, 2014; Lang-Ouellette et al, 2021; Zang and Marder, 2021), which may require more extensive electrophysiological studies.…”