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Neuronal polarity and excitability

13/09/22

Neurons are polarized cells with two defined compartments that differ in morphology and define neuronal function: the axonal and the somatodendritic domains. This asymmetry or polarity is crucial for proper neuronal signaling and communication. These compartments can be further divided into sub‐compartments that can be defined based on their morphology, molecular composition and/or function, such as the synaptic spines on dendrites, the presynaptic boutons in axon terminals, the proximal axon or axonal initial segment (AIS), and the distal axon.

Prickle 2 (Pk2) is a core Planar Cell Polarity (PCP) protein, a particular type of polarity proteins involved in many development processes in most tissues and the favorite topic of research of the Planar Polarity and Plasticity group in Bordeaux.

Pk2, like other PCP proteins, was found initially at the synapse. Pathogenic variants in Prickle genes have been linked to neurodevelopmental disorders (NDDs) such as spina bifida, autism spectrum disorders (ASD) and epilepsy. While defects in spines are believed to be at the roots of the pathologies, Dorrego-Rivas and colleagues found Pk2 at the axon initial segment of the neuron. The AIS not only coordinates axo-dendritic polarity establishment ant maintenance, it has its own plasticity that is essential for tuning neuronal output and hence network coordination in response to changes in input.

In their study in Science Advances, Dorrego-Rivas et al. found Pk2 so early in the polarizing hippocampal neurons that it may well be the first interactor of AnkyrinG-480 (AnkG), the AIS master organizer, helping its stabilization in the one neurite that will become the axon. The function of Pk2 in both the determination of the axon and the formation of the AIS is nicely illustrated when depleting Pk2 and creating a neat multiple axon phenotype with disrupted AIS(s). In addition, the axonal trafficking in these axon is was affected and Pk2 depleted neurons. Pk2-depleted neurons have lower excitability and lack of sodium channel clustering at the AIS, a phenotype reminiscent of AnkG/ANK3 knockout Purkinje neurons.

At least part of the deficits observed is due to the ability of Pk2 to potentiate a microtubule bundling activity of AnkG-480. But because the proteins interact via the ANK repeat of AnkG, common to all isoforms, they could also interact in spines.  The consequences are important as AnkG/ANK3 is a critical gene in ASD, schizophrenia, bipolar disorder, intellectual disability (ID) and epileptic encephalopathy, in both compartments. 

These results show that the presence of the same protein in multiple compartments, engaging in different protein complexes and signaling pathways has important consequence in pathology. When the protein is defective, due to a pathogenic variant of the gene, different compartments may be affected, complicating specific therapeutical approaches. This concept is critically important for complex pathologies like NDDs that still have poorly defined neuronal molecular signatures.

By Ana Dorrego-Rivas, the first author of the story. Ana is currently a postdoc in Matt Grubb’s lab