THE ROLE OF PRICKLE2 IN AXON INITIAL SEGMENT PLASTICITY AND ITS IMPLICATION IN NEURODEVELOPMENTAL PATHOLOGIES

Neuronal plasticity is essential for brain development and maintaining the excitation/inhibition (E/I) balance, the disruption of which is implicated in neurodevelopmental disorders such as epilepsy and autism spectrum disorders.
In the cerebral cortex, parvalbumin (PV)-expressing inhibitory interneurons play a key role in regulating pyramidal neuron activity via axo-axonic synapses targeting the axon initial segment (SIA). The SIA is a highly specialized and dynamic neuronal domain, crucial for action potential initiation and sensitive to neuronal activity.
We show that the planar cell polarity protein Prickle2 (Pk2) is essential for maintaining SIA integrity in hippocampal and cortical neurons. Pk2 interacts with ankyrin G (AnkG), a central SIA protein (Dorego-Rivas et al., 2022). The Pk2–AnkG interaction promotes microtubule organization necessary for the assembly and maintenance of the AIS structure. Loss of Pk2 leads to marked morphological abnormalities of the axon initial segment (AIS), associated with cytoskeletal disorganization, reduced AnkG accumulation, and altered neuronal excitability.
In this study, we explore whether and how neuronal plasticity is affected by the selective deletion of Pk2 in PV interneurons, using a mouse model (PV*Pk2). Our results reveal deficits in social and working memory in male and female PV*Pk2 mice, suggesting that loss of Pk2 in PV GABAergic circuits could contribute to autism spectrum disorder (ASD)-like phenotypes.
Our work, focusing on PV interneurons, aims to determine how the regulation of AIS morphology dependent on Pk2 influences cortical plasticity and the excitation/inhibition (E/I) balance.