Sensory input drives rapid homeostatic scaling of the axon initial segment in mouse barrel cortex

Nora Jamann, Dominik Dannehl, Robin Wagener, Corinna Corcelli, Christian Schultz, Jochen Staiger, Maarten H.P. Kole, Maren Engelhardt

Preprint posted on 28 February 2020

Article now published in Nature Communications at

And yet it moves! Sensory input drives AIS changes in length in the mouse barrel cortex

Selected by Ana Dorrego-Rivas

Categories: neuroscience

Background and introduction

In most neurons, the axon initial segment (AIS) is the site for action potential generation and tuning, due to its high concentration of voltage-gated channels. While the AIS has a strong molecular network, multiple studies revealed an activity-dependent structural plasticity to maintain neuronal homeostasis. In cultured neurons, the AIS can change in position as a response to chronic depolarization. However, these changes in position and/or length seem to vary within neuronal type, making AIS plasticity a more complex matter.

The AIS of cultured hippocampal neurons shifts away from the soma under chronic depolarization conditions. The staining is for AnkyrinG, the master organizer of the structure. Image from Grubb MS and Burrone J. “Activity dependent relocation of the axon initial segment fine-tunes neuronal excitability”, Nature, 2010


In vivo, AIS structural plasticity can happen during development, like in the virtual cortex, but also in the context of sensory deprivation: the AIS from neurons of the nucleus magnocellularis changes in length when facing a lack of auditory stimuli. Still, the current knowledge we have about AIS remodeling and how it translates to maintain neuronal excitability in the brain circuits is limited. In this study, the authors use the mouse whisker-to-barrel system, a very well-known studied sensory pathway, to study AIS plasticity in a behaviorally relevant context.


Key findings

The authors first sought to monitor the length of the AIS of pyramidal neurons in layers II/III and V of the primary somatosensory cortex (SF1B) within different developmental timepoints. For that, they used immunolabelling on brain slices for ßIV-spectrin, one of the key molecules of the AIS, and found the structure to be particularly dynamic: the AIS length increased notably between the beginning and the second week of the postnatal period and then shortened to keep an average length. This AIS lengthening was followed by an overall increase of AnkyrinG (AnkG), the master organizer of the AIS, in all of its isoforms.

In green, example of an AIS staining in the neuron. The somatodendritic compartment and the spines are visible in pinkJamann et al., in revision.


Since the period of AIS length reduction coincides with the onset of active whisking behavior, the authors hypothesized that this activity is the one modulating the AIS structural maturation. To test it, they focused on a sensory-deprivation strategy consisting in trimming the whiskers at the moment of birth and observe the AIS structure after 15, 21 and 45 days. Neurons from layers II/III displayed a lengthening of the AIS in all the tested conditions as a response to the deprivation, but those from layer V remained unaffected. To assess if this scenario was reversible with a recovery of the sensory input, the authors trimmed the whiskers of the mouse, let them grow back and then assessed AIS structure: the length went back to mature levels. Interestingly, when whisker trimming was performed in older animals, the AIS also increased in length in the same layers. These striking results are a proof that AIS plasticity at the primary somatosensory cortex is sensory-input dependent even in the adult brain!

But, how do these structural changes translate to the excitability of the neurons? The authors performed patch-clamp recordings in layer II/III neurons in control and sensory-deprived mice. After confirming no changes in the resting membrane potential, they found that the action potential firing rates were higher for the mice with shorter whiskers and that the current they needed to inject to fire an action potential was lower. After performing a post-hoc staining of the recorded neurons, the authors confirmed a correlation between the length of the AIS and the increased intrinsic excitability of layer II/III neurons.

The data confirms a reduction of the AIS length with a progressive recovery of the sensory input within hours, however, is it possible to induce a faster re-structuration? To answer this, the authors used an enriched environment (EE) where the mice were placed for different timings — 1h, 3h and 6h. This time, whiskers were trimmed unilaterally (and not bilaterally as the previous experiments), implying that that the SF1B contralateral to the intact whisker side (here referred to as “EE”) received higher activation by the whisker-to-barrel pathway than the ipsilateral side, which represents the control. After confirming the activation of the network through c-fos staining, the authors observed a decrease in length of the AIS in the EE neurons in all the measured timepoints. The exposition of the animals to a sensory enriched environment triggers a faster AIS relocation! Notably, when the mice were placed in the EE for 3h and put back for other 3h at the basal environment, the AIS remained unchanged. Again, this was true for neurons from layers II/III but not for those from layer V. Altogether, these powerful results reveal a very quick and adaptive AIS behavior to different sensory inputs.

To assess the impact of these fast changes in neuronal excitability, the authors performed electrophysiology recordings in control and EE neurons of layers II/III. In line with the findings above, the EE neurons displayed a higher threshold and frequency of firing action potentials versus the control, revealing an overall reduced intrinsic excitability.

In conclusion, this study makes a step forward on understanding AIS plasticity in vivo and, more specifically, within a concrete behavior context. It will definitely be the start of further studies on how these excitability changes integrate in the whole network and, therefore, in the brain.


Why did I choose this article?

I am a huge passionate about the AIS and the plasticity field and I appreciate the high quality of this work. Not a lot is known about the AIS role on maintaining neuronal homeostasis in vivo, and this study covers a big part of it. Some studies were performed on the auditory system, but this one is pioneer on this kind of sensory information (tactile) and the whisker-to-barrel pathway.

The way the article is written, first addressing the structural changes and then the functional ones, makes it easier and enjoyable to read. It is also based on scientific statements provided by numerous repetitions of experiments and trustable statistics. Scientific robustness is a must for all the researchers. I also found the discussion very complete, covering all the aspects to which the data did not have the exact answer.



Evans, M.D., Dumitrescu, A.S., Kruijssen, D.L., Taylor, S.E., and Grubb, M.S. (2015). Rapid Modulation of Axon Initial Segment Length Influences Repetitive Spike Firing. Cell Rep 13, 1233-1245.

Galiano, M.R., Jha, S., Ho, T.S., Zhang, C., Ogawa, Y., Chang, K.J., Stankewich, M.C., Mohler, P.J., and Rasband, M.N. (2012). A Distal Axonal Cytoskeleton Forms an Intra- Axonal Boundary that Controls Axon Initial Segment Assembly. Cell 149, 1125-1139.

Grubb, M.S., and Burrone, J. (2010). Activity-dependent relocation of the axon initial segment fine-tunes neuronal excitability. Nature 465, 1070-1074.

Gutzmann, A., Ergul, N., Grossmann, R., Schultz, C., Wahle, P., and Engelhardt, M. (2014). A period of structural plasticity at the axon initial segment in developing visual cortex. Front Neuroanat 8, 11.

Kuba, H., Oichi, Y., and Ohmori, H. (2010). Presynaptic activity regulates Na(+) channel distribution at the axon initial segment. Nature 465, 1075-1078.







Tags: ais, behavior, plasticity, whisker-to-barrel

Posted on: 10 April 2020


Read preprint (2 votes)

Author's response to the proposed questions

Nora Jamann and Maren Engelhardt shared

1- Your data goes in line with some studies about AIS plasticity: a longer AIS leads to a higher excitability and vice versa. Did you have the chance to check the levels of Nav channels in the sensory-deprived neurons? Do you think that you would see a higher density that can explain the increase of excitability?

“We did not check the density of sodium channels in the sensory-deprived neurons, since to precisely determine sodium channel density one needs to patch the AIS, which is technically very challenging. Currently, the existing literature supports the hypothesis that AIS length changes cause alterations in excitability with the increased or decreased isolation of the distal initiation site from the capacitive current sink at the soma (see Kole and Brette, Current opinion in Neurobiology, 2018). However, that density changes on the level of ion channels occur is a possibility and needs to be explored further.”

2-Your findings apply for the layers II/III but not for the V. You discuss the possibility of different roles for both within development, but is it possible that layer V neurons could show another kind of plasticity (not AIS related) in response to the sensory deprivation?

“Indeed, that is a possibility. In both populations (layers II/III and V), we cannot exclude that plasticity is also occurring e.g. at the synaptic level (bot pre- and postsynaptic site). We however hypothesize that these forms of homeostatic scaling do not exclude each other but rather work hand in hand to regulate the input-output equilibrium at different neuronal sites.”

3-Do you know if your results can apply to a pathology context? Is there any disease that involves this kind of deprivation?

“There are a great number of studies linking AIS dysfunction to nervous system disease. One of the most notable is the discovery of the ANK3 gene (encodes Ankyrin-G), as psychiatric risk factor for bipolar disorder and schizophrenia. Furthermore, AIS channel dysfunction has been linked to epilepsy and autism spectrum disorders (for review see: Buffington and Rasband, European Journal of Neuroscience, 2011). Based on our findings and previous studies it seems evident that if AIS plasticity is disrupted, homeostatic regulation of neuronal output as a response to altered synaptic input will be severely impaired, which in turn can lead to dysfunction of the whole network. However, the exact mechanisms underlying this link remain yet to be investigated in detail.”

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