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Interactions Among Diameter, Myelination, and the Na/K Pump Affect Axonal Resilience to High-Frequency Spiking

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Interactions Among Diameter, Myelination, and the Na/K Pump Affect Axonal Resilience to High-Frequency Spiking Interactions among diameter, myelination, and the Na/K pump affect axonal resilience to high-frequency spiking Yunliang Zanga,b and Eve Mardera,b,1 aVolen National Center for Complex Systems, Brandeis University, Waltham, MA 02454; and bDepartment of Biology, Brandeis University, Waltham, MA 02454 Contributed by Eve Marder, June 22, 2021 (sent for review March 25, 2021; reviewed by Carmen C. Canavier and Steven A. Prescott) Axons reliably conduct action potentials between neurons and/or (16–21). It remains unknown how these directly correlated pro- other targets. Axons have widely variable diameters and can be cesses, fast spiking and slow Na+ removal, interact in the control myelinated or unmyelinated. Although the effect of these factors of reliable spike generation and propagation. Furthermore, it is on propagation speed is well studied, how they constrain axonal unclear whether reducing Na+-andK+-current overlap can con- resilience to high-frequency spiking is incompletely understood. sistently decrease the rate of Na+ influx and accordingly enhance Maximal firing frequencies range from ∼1Hzto>300 Hz across axonal reliability to propagate high-frequency spikes. Conse- neurons, but the process by which Na/K pumps counteract Na+ quently, by modeling the process of Na+ removal in unmyelinated influx is slow, and the extent to which slow Na+ removal is com- and myelinated axons, we systematically explored the effects of patible with high-frequency spiking is unclear. Modeling the pro- diameter, myelination, and Na/K pump density on spike propagation cess of Na+ removal shows that large-diameter axons are more reliability. resilient to high-frequency spikes than are small-diameter axons, because of their slow Na+ accumulation. In myelinated axons, the Results myelinated compartments between nodes of Ranvier act as a “res- Different [Na+] Decay Dynamics in Unmyelinated and Myelinated + ervoir” to slow Na accumulation and increase the reliability of Axons. We implemented multicompartment models of axons in axonal propagation. We now find that slowing the activation of NEURON (23). Both the unmyelinated and the myelinated axon NEUROSCIENCE K+ current can increase the Na+ influx rate, and the effect of min- models include INa,IKD,IKA,Ileak, and the Na/K pump. All + + imizing the overlap between Na and K currents on spike propa- channels and pumps were evenly spread in the unmyelinated axon gation resilience depends on complex interactions among diameter, model and at the nodes of Ranvier in the myelinated axon model. myelination, and the Na/K pump density. Our results suggest that, For the myelinated compartments, there is a significantly lower in neurons with different channel gating kinetic parameters, differ- density of Ileak and Cm to simulate the effect of insulation (Ma- ent strategies may be required to improve the reliability of axonal terials and Methods). The model structures are shown in Fig. 1A. propagation. Spikes propagate rapidly in both models. In the unmyelinated axon model, the propagation increases from 0.10 m/s to 0.30 m/s computational model | action potential | node of Ranvier | electrogenic when the axonal diameter increases from 0.2 μmto1μm. In the pumps | sodium dynamics myelinated axon model, the speed increases from 0.87 m/s to xons usually reliably conduct information (spikes) to other Significance Aneurons, muscles, and glands. The largest-diameter axons are found in some invertebrates, where the squid giant axon and The reliability of spike propagation in axons is determined by arthropod giant fibers are parts of rapid escape systems. In the complex interactions among ionic currents, ion pumps, and mammalian nervous system, axon diameters can differ by a fac- > morphological properties. We use compartment-based model- tor of 100. Some are covered with myelin sheaths but others are ing to reveal that interactions of diameter, myelination, and not (1). Both myelination and large axon diameter increase spike the Na/K pump determine the reliability of high-frequency propagation speed (2, 3), and the latter factor can also increase spike propagation. By acting as a “reservoir” of nodal Na+ in- axonal resilience to noise perturbation (4). flux, myelinated compartments efficiently increase propaga- Neuronal firing frequency is not static, but variations in firing tion reliability. Although spike broadening was thought to rates are used to encode a wide range of signals such as inputs oppose fast spiking, its effect on spike propagation is com- from sensory organs and command signals from motor cortex. plicated, depending on the balance of Na+ channel inactivation The maximal firing frequency, critical for neuronal functional + ∼ > – gate recovery, Na influx, and axial charge. Our findings suggest capacity, ranges from 1Hzto 300 Hz (5 8). However, it re- that slow Na+ removalinfluencesaxonalresiliencetohigh- mains unclear how axonal physical properties constrain axonal + frequency spike propagation and that different strategies may resilience to high-frequency firing. During action potentials, Na be required to overcome this constraint in different neurons. flows into axons and then adenosine 5′-triphosphate (ATP) is + used by Na/K pumps to pump out the excess Na . Given the Author contributions: Y.Z. and E.M. designed research; Y.Z. performed research; Y.Z. an- limited energy supply in the brain, evolutionary strategies includ- alyzed data; and Y.Z. and E.M. wrote the paper. ing shortening spike propagation distance, sparse coding, and re- Reviewers: C.C.C., Louisiana State University Health Sciences Center New Orleans; and + + ducing Na -andK -current overlap, and so on, have helped S.A.P., Great Ormond Street Hospital for Children NHS Foundation Trust. minimize energy expenditure (9–13). However, the observation The authors declare no competing interest. that high-frequency spiking tends to occur in large-diameter axons This open access article is distributed under Creative Commons Attribution-NonCommercial- (5) is confusing, because fast spiking in large-diameter axons NoDerivatives License 4.0 (CC BY-NC-ND). + causes more Na influx and exerts a heavy burden on the energy 1To whom correspondence may be addressed. Email: [email protected]. supply in the brain (14, 15). Additionally, the process by which This article contains supporting information online at https://www.pnas.org/lookup/suppl/ Na/K pumps remove Na+ is slow (16–22). In neurons, it takes sec- doi:10.1073/pnas.2105795118/-/DCSupplemental. + + onds or even minutes to remove the excess Na after [Na ]elevation Published August 5, 2021. PNAS 2021 Vol. 118 No. 32 e2105795118 https://doi.org/10.1073/pnas.2105795118 | 1of7 Downloaded by guest on September 30, 2021 A unmyelinated myelinated Na+ 20 mV 2 ms Na+ ATP ADP ATP ADP ATP ADP ATP ADP + Pi + Pi + Pi B + Pi ] ] + + node 0.2 mM [Na 2 sec [Na myelin C diameter diameter 1 0.2 μm 0.6 μm 1.0 μm 1 0.2 μm 0.6 μm 1.0 μm pump density ] (mM) ] (mM) + 0.5 baseline + 0.5 baseline×10 [Na [Na 0 0 025500255002550 00.3 0.6 00.3 0.6 0 0.3 0.6 time (sec) time (sec) time (sec) time (sec) time (sec) time (sec) Fig. 1. Spike-triggered [Na+] rise and decay in unmyelinated and myelinated axon models. (A) Schematics of the unmyelinated (Left) and the myelinated (Right) axon models. Black traces show spike waveforms in the two models (50 μm from the distal axon end; in the myelinated model it is also a node of Ranvier). (B) Spike-triggered [Na+] rise and decay in the unmyelinated (Left) and the myelinated (Right) axon models. Black traces were measured at cor- responding voltage recording sites. Green trace shows [Na+] in the myelinated compartment (16.7 μm from the node of Ranvier) and the initial part is en- larged in the inset. The Na/K pump density is 0.5 pmol/cm2, referred to as baseline condition hereafter. (C) The effects of diameter and pump density on [Na+] rise and decay in the unmyelinated (Left) and the myelinated (Right, at the node of Ranvier) axon models. Note the very different time scales in the two models. 2.09 m/s accordingly. Upon the arrival of spikes, Na+ channels accumulation speed increases with firing frequency because of a open and extracellular Na+ flows into axons to raise the intra- faster Na+ influx rate (Fig. 2A). Larger SVRs can also make Na+ cellular [Na+] immediately (Fig. 1B). Then, K+ currents are accumulate faster in thin axons. Note that the seemingly slower activated to repolarize the spikes. Compared with the other ionic Na+ accumulation in the 0.2-μm-diameter axon at 60 Hz is due currents, the magnitude of the Na/K pump current is extremely to earlier propagation failure. In parallel with Na+ accumulation, small during a single spike, but it decays very slowly. Eventually, the Na+ equilibrium potential (driving force of Na+ current) the Na/K pump gradually removes Na+ from the axon, leading becomes more negative and the action potential peak decreases to a slow, many-second [Na+] decay in the unmyelinated axon (Fig. 2 B and C). With increased firing frequency, propagation model (Fig. 1 B, Left). In contrast, in the myelinated axon model, starts to fail. The failure starts from 30 Hz in the 0.2-μm-diameter the spike-triggered [Na+] elevation at the node of Ranvier de- axon (Fig. 2C) but from 60 Hz in larger-diameter axons. A rep- cays on the time scale of hundreds of milliseconds (Fig. 1 B, ertoire of propagation failure patterns was observed. In Fig. 2 D, Right). The Na/K pump densities in the two models are the same 1, every other spike propagated through the axon, but a more and thus the quick decay is not a result of superefficient pumps. complicated propagation failure pattern is shown in Fig. 2 D, 2. + In the myelinated axon model, Na+ channels are placed only in When the model fires over a sufficiently long period, the Na the nodes of Ranvier and there is no transmembrane Na+ influx influx rate and efflux rate gradually balance each other to make + in the myelinated compartments.
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