Axon Initial Segment Biology

The axon initial segment is a key compartment in neurons, it is the site of action potential generation. The axon initial segment structure is actively reorganized to accommodate changes in network activity, making this structure an active checkpoint for signal integration. The aim of our research is to unveil the molecular mechanisms controlling axon initial segment plasticity. We want to understand how neurons can adapt to their environment and how this process is altered in neurological disorders.


Axon Initial Segment Biology

The axon initial segment (AIS) is a neuronal compartment, sitting at the base of the axon and specialized in the generation of action potentials. The axon initial segment is a critcal checkpoint in the propagation of information throughout neuronal networks: after integration of somato-sendritic inputs, the axon initial segment determines the neuron’s output, which will then be further transmitted along the axon to the next neurons in the network. The molecular organization of the AIS, in particular the distribution and density of ion-channels, defines action potential threshold and characteristics. Previous work from our group and others showed that the AIS is highly plastic and its morphology is altered upon changes in network activity. The adaptive behavior of the AIS makes it a very important site of signal integration and an active player in the maintenance of network homeostasis.
The aim of our research is to unveil the molecular mechanisms controlling AIS remodeling in response to changes in activity level. We want to understand how neurons can adapt their firing properties to the environment and how this process is altered in neurological disorders.

Research focus

Our general aim is to understand the molecular mechanisms of AIS plasticity.
To do so, we assess the nanoscale (re)organization of AIS components during plasticity using super-resolution microscopy combined with CRISPR-Cas9 labeling strategies. We then explore how this reorganization is controlled, using live-cell imaging and proteomic approaches. We perform these experiments in several models, cultured rodent neurons as well as human iPSC derived neurons. This latter system is insightful to understand if and how AIS plasticity is altered in various neurological disorders and how in turn this alteration participates to the pathophysiology. Combining advanced imaging techniques with genome editing approaches in disease-relevant systems allow us to better understand how neurons can shape their activity and adapt to changes in their environments in health and disease.

Open positions

We are currently looking for a PhD student to join us from July 2022.
Master students are welcome to apply for an internship in the lab. And we are always happy to hear from motivated people who wants to bring in their ideas, please reach out!

For the latest news, please check out @FreAmeLie

Selected publications

Freal, A., Rai, D., Tas, R.P., Pan, X., Katrukha, E.A., van de Willige, D., Stucchi, R., Aher, A., Yang, C., Altelaar, A.F.M., et al. (2019). Feedback-Driven Assembly of the Axon Initial Segment. Neuron.

Freal, A., Fassier, C., Le Bras, B., Bullier, E., De Gois, S., Hazan, J., Hoogenraad, C.C., and Couraud, F. (2016). Cooperative Interactions between 480 kDa Ankyrin-G and EB Proteins Assemble the Axon Initial Segment. J Neurosci 36, 4421-4433.

Le Bras, B.*, Freal, A. , Czarnecki, A., Legendre, P., Bullier, E., Komada, M., Brophy, P.J., Davenne, M., and Couraud, F. (2014). In vivo assembly of the axon initial segment in motor neurons. Brain Struct Funct 219, 1433-1450.

Kuijpers, M., van de Willige, D., Freal, A., Chazeau, A., Franker, M.A., Hofenk, J., Rodrigues, R.J., Kapitein, L.C., Akhmanova, A., Jaarsma, D., et al. (2016). Dynein Regulator NDEL1 Controls Polarized Cargo Transport at the Axon Initial Segment. Neuron 89, 461-471.

Farias, G.G., Freal, A., Tortosa, E., Stucchi, R., Pan, X., Portegies, S., Will, L., Altelaar, M., and Hoogenraad, C.C. (2019). Feedback-Driven Mechanisms between Microtubules and the Endoplasmic Reticulum Instruct Neuronal Polarity. Neuron 102, 184-201 e188.

Fassier, C., Freal, A., Gasmi, L., Delphin, C., Ten Martin, D., De Gois, S., Tambalo, M., Bosc, C., Mailly, P., Revenu, C., et al. (2018). Motor axon navigation relies on Fidgetin-like 1-driven microtubule plus end dynamics. J Cell Biol.

Harterink, M., Vocking, K., Pan, X., Soriano Jerez, E.M., Slenders, L., Freal, A., Tas, R.P., van de Wetering, W.J., Timmer, K., Motshagen, J., et al. (2019). TRIM46 organizes microtubule fasciculation in the axon initial segment. J Neurosci.