Sensory input drives rapid homeostatic scaling of the axon initial segment in mouse barrel cortex
Preprint posted on 28 February 2020 https://www.biorxiv.org/content/10.1101/2020.02.27.968065v1
Article now published in Nature Communications at http://dx.doi.org/10.1038/s41467-020-20232-x
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.
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.
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.
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.
Posted on: 10 April 2020Read preprint
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