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# Somatic modulation of ectopic action potential initiation in distal axons

Aurélie Fékété, Dominique Debanne

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Aurélie Fékété, Dominique Debanne. Somatic modulation of ectopic action potential initiation in distal axons. The Journal of Physiology, 2018, 596 (21), pp.5067-5068. 10.1113/jp277012. hal-01963294

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Submitted on 21 Dec 2018

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Distributed under a Creative Commons Attribution 4.0 International License
Somatic modulation of ectopic
action potential initiation
in distal axons

Aurélie Fékété
and Dominique Debanne

UNIS, UMR-1072, INSERM, Aix-
Marseille University, Marseille, France

Email: dominique.debanne@inserm.fr

Edited by: Ole Paulsen & Diego Contreras

Classically, action potentials are initiated at the axon initial segment (AIS) when the summed depolarizing events arising from the dendrites exceed a threshold value. Then, action potentials propagate along the axon before reaching presynaptic terminals where they cause local calcium influx and transmitter release. According to this scheme, the AIS is a major player since all propagated excitation is precisely initiated at this hot spot endowed with a high concentration of sodium channels. However, sodium action potentials may be generated at regions remote from the AIS, that is, at ectopic sites located in the axon.

Ectopic action potentials (EAPs) can be initiated in distal parts of the axon and travel antidromically along the fibre to invade the soma. Such ectopic spikes have been recorded during fast hippocampal oscillations *in vitro* (Dugladze *et al.* 2012) or during spatial exploration *in vivo* (Epsztein *et al.* 2010), but they also occur in several neuronal pathologies such as epilepsies or demyelinating diseases. The precise way EAPs can be initiated is not yet properly defined but it is thought that local depolarization mediated by spiking activity in adjacent axons through gap junctions (Schmitz *et al.* 2001) or stochastic activation of sodium channels in demyelinated segments of the axon (Hamada & Kole, 2015) might initiate EAPs. Compared to AIS-evoked action potentials that are classically initiated on the top of a slow subthreshold depolarization such as an excitatory postsynaptic potential, EAPs recorded in the cell body display a much lower threshold (~ -20 mV) (Hamada & Kole, 2015). This lower threshold is thought to result from the axial current flow initiated distally in the axon that propagates back to the soma. In this case, the spike is initiated without subthreshold

depolarization generated in the soma, thus avoiding inactivation of sodium channels in the axon. The backpropagation of EAPs is controlled by synaptic inhibition mediated by axo-axonic interneurons that target the AIS (Dugladze *et al.* 2012). As a result, most of EAPs do not propagate to the soma during hippocampal gamma oscillations. While the control of EAP backpropagation has been characterized, it was yet unknown to what extent synaptic potentials arising from the somato-dendritic pole can control their initiation in the axon.

In this issue of *The Journal of Physiology*, Thome and coworkers (2018) have answered this question by showing that spontaneous or evoked synaptic activity generated in the somato-dendritic compartment is transmitted with little attenuation (~20%) and over long distances (>300 µm) in axons of CA1 pyramidal cells (Thome *et al.*, 2018). Voltage transients were even amplified in the proximal region of the axon. For this, the authors obtained simultaneous whole-cell patch-clamp recordings from the soma and the axon of individual CA1 pyramidal neurons and they compared amplitudes of excitatory postsynaptic potentials (EPSPs) measured in the somatic and axonal compartments. While synaptic responses displayed little attenuation when recorded in the axon, the opposite was not verified since subthreshold potentials generated in the axon were found to be strongly attenuated in the somatic compartment (~85%). Next, Thome *et al.* examined the role of evoked excitatory and inhibitory synaptic potentials in the generation of EAPs. The probability of evoking an EAP by extracellular stimulation of the alveus was greatly enhanced when EPSPs were evoked simultaneously (Thome *et al.*, 2018). In contrast, EAPs were less successful when inhibitory postsynaptic potentials (IPSPs) were evoked with an extracellular stimulating electrode located near the soma. The relative timing between synaptic responses and EAP was found to be critical, suggesting the possible contribution of such a mechanism in fast network oscillations. Thus, the findings of Thome and coworkers strongly suggest that modulation of ectopic excitability depends on propagation of somatic voltage deflections to the axonal site of EAP initiation in a time-dependent manner.

This paper is important because it opens
several interesting perspectives. First, the
fact that synaptic inputs arising from the
somato-dendritic region modulate EAP
initiation challenges the view that the distal
axon is electrically independent from the
soma. In fact, recent estimations of the
space constant in axons give values ranging
between ~200 and ~1000 µm, depending
on the cell type. The originality of the
findings of Thome et al. resides in the fact
that the space constant in the axon of CA1
pyramidal neurons was found to be highly
polarized towards the axonal pole, due
to the difference in somatic and axonal
capacitance. Second, the facilitation of EAP
induction caused by synaptic excitation
may prove to be a factor aggravating cellular
hyperexcitability and epileptic network
discharges under pathological conditions.
In addition, the time dependence of ectopic
firing modulation by synaptic inputs
suggests that this process may contribute
to the high precision of action potential
timing during fast network oscillations.
Most previous studies devoted to the
coupling between somatic and axonal
compartments have focused on describing
the impact of axonal ion channels on
firing properties measured in the cell body
(Kole, 2011; Rama et al. 2017). The original
contribution of Thome et al.'s findings
resides in showing that electrical activity at
the input side is detected by the axon over
long distances to determine whether an
EAP can be triggered or not. In this study,
EAPs were evoked by electrical stimulation
of distal axons. Future studies will have to
identify precisely the trigger and the site
of initiation of EAPs in axons. There is no
doubt that these questions will be quickly
resolved.

References

Dugladze T, Schmitz D, Whittington MA, Vida I & Gloveli T (2012). Segregation of axonal and somatic activity during fast network oscillations. *Science* **336**, 1458–1461.

Epsztein J, Lee AK, Chorev E & Brecht M (2010).
Impact of spikelets on hippocampal CA1
pyramidal cell activity during spatial
exploration. *Science* **327**, 474–477.

Hamada MS & Kole MH (2015). Myelin loss and
axonal ion channel adaptations associated
with gray matter neuronal hyperexcitability.
*J Neurosci* **35**, 7272–7286.
Perspectives

Kole MH (2011). First node of Ranvier facilitates high-frequency burst encoding. *Neuron* **71**, 671–682.

Rama S, Zbili M, Fekete A, Tapia M, Benitez MJ, Boumedine N, Garrido JJ & Debanne D (2017). The role of axonal Kv1 channels in CA3 pyramidal cell excitability. *Sci Rep* **7**, 315.

Schmitz D, Schuchmann S, Fisahn A, Draguhn A, Buhl EH, Petrasch-Parwez E, Dermietzel R, Heinemann U & Traub RD (2001).
Axo-axonal coupling: a novel mechanism for ultrafast neuronal communication. *Neuron*
**31**, 831–840.

Thome C, Roth FC, Obermayer J, Yanez A, Draguhn A & Egorov AV (2018). Synaptic entrainment of ectopic action potential generation in hippocampal pyramidal neurons. *J Physiol* **596**, 5237–5249.

**Additional information**

**Competing interests**

None declared.

**Funding**

Supported by INSERM, CNRS & ANR (ANR-14-CE13-003).

**Author contributions**

Both authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.