<figure><img src="image_1.png" /></figure>

PERSPECTIVE

cAMP reduces action potential
amplitude and conduction
velocity over long axonal
distance

Fabrice Abate, Chaima Ajal
and Dominique Debanne

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

Email: dominique.debanne@univ-amu.fr

Handling Editors: Katalin Toth & Samuel
Young

The peer review history is available in
the Supporting information section
of this article (https://doi.org/10.1113/
JP287264#support-information-section).

Presynaptic neurotransmitter release at
both excitatory and inhibitory synapses is
highly controlled by cAMP. For example,
the production of cAMP is responsible

for long-term potentiation (LTP) at
hippocampal mossy fibre synapses that
is a result of the increased glutamate
release. Indeed, cAMP shortens the
coupling distance between presynaptic
voltage-gated calcium channels and the
release machinery (Fukaya et al., 2021),
and thus elevates the efficacy of presynaptic
calcium to trigger neurotransmitter release.
Synaptic transmission is also under the
control of the presynaptic action potential
(AP) that, in contrast to the classical dogma,
may vary in amplitude according to the
context in which it is generated and may
thus determine the output signal in an
analogue-digital way (Rama et al., 2015;
Zbili et al., 2020). However, the effect of
cAMP on the presynaptic AP is largely
unknown.

In this issue of *The Journal of Physio-
logy*, Furukawa et al. (2024) have elegantly
solved this question by showing that axon
AP amplitude is reduced by cytoplasmic

cAMP through the inhibition of the sodium
current in the axonal compartment. Using
a very distinguished combination of paired
-recordings from Purkinje cells and deep
cerebellar nuclei neurons maintained in
culture and patch clamp recording from
thin axons and presynaptic terminals
(Kawaguchi & Sakaba, 2015), it is shown
that, at short axonal paths, synaptic trans-
mission is slightly enhanced, whereas at
long axonal paths, synaptic transmission is
reduced and delayed in time (Fig. 1). Then,
Furukawa et al. (2024) show that these two
effects observed at distal output synapses
are a result of the reduction of the sodium
current but not calcium current. Thus, for
proximal synapses (~250 µm), the axonal
length is too short to produce a significant
effect, but not for distal synapses (~800
µm) because the inhibition of sodium
channels is cumulative in the latter case.
This effect does not involve the cAMP
sensor, Epac, as Epac inhibitors have no

<figure><img src="image_2.png" /><figcaption>**Figure 1.** cAMP reduces action potential amplitude and conduction velocity over long axonal distances</figcaption></figure>

Left: scheme of a Purkinje cell with proximal and distal synapses. At proximal synapses, the cAMP-dependent inhibition of voltage-gated sodium channel (Nav) has no effect on the amplitude of the action potential and the release of GABA is possibly augmented through the reduction of the coupling distance between voltage-gated calcium channels (Cav) and the release machinery. By contrast, at distal synapses, the cumulative inhibition of Nav channels over a long distance reduces both the amplitude and the conduction velocity, thus reducing GABA release.
effect on cAMP-induced down-regulation of axonal sodium channels. However, PKA mediates this down-regulation of sodium channels.

The study by Furukawa et al. (2024) is of great importance for several reasons. First, it shows that a single factor (i.e. cAMP) is able to differentially modulate proximal and distal outputs through the increased release at proximal synapses and the specific inhibition of axonal sodium channels that in turn reduces the amplitude of the AP and slows down its conduction at distal synapses. Such a differential effect is not common. Proximal synapses established by Purkinje cells usually correspond to local contacts on other Purkinje cells or to autaptic contacts (i.e. self-inhibitory). In other cell types such as cortical pyramidal neurons, proximal inputs locally target other pyramidal neurons. In addition, this remarkable study confirms that the fine tuning of AP amplitude has major consequences on synaptic transmission and synaptic delay. The increased synaptic delay is due to the reduction in the conduction velocity as a result of sodium channel inhibition. The study by Furukawa et al. (2024) also opens several fundamental questions. First, sodium channels are inhibited by many neuromodulators such as dopamine, serotonin or ACh through protein kinase A or protein kinase C and there are good reasons to assume that these neuromodulators may also induce similar reductions in both synaptic transmission and conduction speed at distal output synapses. In addition, the study shows that the AP amplitude is reduced in the axonal compartment but not in the

somatic compartment, suggesting that the function of sodium channels is near critical in the axon because of a low density and/or a larger inactivation of axonal sodium channels compared to somatic ones. There is little doubt that future studies will address all these pending issues.

## References

Fukaya, R., Maglione, M., Sigrist, S. J., & Sakaba, T. (2021). Rapid Ca2+ channel accumulation contributes to a cAMP-mediated increase in transmission at hippocampal mossy fiber synapses. *Proceedings of the National Academy of Sciences of the United States of America*, **118**(9), e2016754118.

Furukawa, K., Inoshita, T., & Kawaguchi, S. (2024) Graded control of Purkinje cell outputs by cAMP through opposing action on axonal action potential and transmitter release. *The Journal of Physiology, Advance online publication*. https://doi.org/10.1113/JP286668

Kawaguchi, S., & Sakaba, T. (2015). Control of inhibitory synaptic outputs by low excitability of axon terminals revealed by direct recording. *Neuron*, **85**(6), 1273–1288.

Rama, S., Zbili, M., Bialowas, A., Fronzaroli-Molinieres, L., Ankri, N., Carlier, E., Marra, V., & Debanne, D. (2015). Presynaptic hyperpolarization induces a fast analogue modulation of spike-evoked transmission mediated by axonal sodium channels. *Nature Communications*, **6**, 10163.

Zbili, M., Rama, S., Yger, P., Inglebert, Y., Boumedine-Guignon, N., Fronzaroli-Moliniere, L., Brette, R., Russier, M., & Debanne, D. (2020). Axonal Na+ channels detect and transmit levels of input synchrony in local brain circuits. *Science Advances*, **6**(19), eaay4313.

## Additional information

### Competing interests

No competing interests declared.

### Author contributions

All authors have approved the final version of the manuscript submitted for publication 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.

### Funding

Agence Nationale de la Recherche (ANR): Dominique Debanne, ANR-23-CE16-0020-01; Agence Nationale de la Recherche (ANR): Dominique Debanne, ANR-21-CE16-0013-01.

### Keywords

action potential, axon, cerebellum, conduction, neuron

## Supporting information

Additional supporting information can be found online in the Supporting Information section at the end of the HTML view of the article. Supporting information files available:

### Peer Review History