Axon initial segment damage and hyperexcitability in a mutant mouse with increased calpain-dependent cleavage of αII-Spectrin

The cytoskeleton is essential for maintaining the structural integrity of axons and the axon initial segment (AIS), a specialized domain located at the axon shaft that plays a critical role in regulating neuronal excitability. Among cytoskeletal components, spectrins are key structural proteins that help to maintain the integrity of axons. Mutations in SPTAN1, the gene coding for αII-spectrin, are linked to a group of neurodevelopmental disorders known as SPTAN1 encephalopathies. These disorders are characterized by developmental and epileptic encephalopathies, with clinical features including brain atrophy, hypomyelination, developmental delay, intellectual disability, infantile spasms, and seizures. However, a clear genotype-phenotype relationship remains elusive. In this study, we investigated a novel mouse model carrying the R1098Q point mutation within the tenth triple-helical repeat of αII-spectrin. This mutation destabilizes the protein's structure and increases its sensitivity to calpain-dependent degradation. Similar mutations in humans are believed to disrupt electrostatic interactions necessary for proper αII-spectrin folding, contributing to disease pathogenesis. The primary goal of this study was to determine how the R1098Q mutation affects AIS integrity and contributes to brain hyperexcitability and seizure susceptibility. Our results show that R1098Q mutant mice display abnormal electroencephalographic activity, increased neuronal excitability, and heightened sensitivity to a chemoconvulsant. Morphological analysis revealed fewer AIS structures, along with structural defects such as shortening and thinning of these segments. Overall, this study provides new insight into how specific SPTAN1 mutations may lead to neurodevelopmental disorders. The R1098Q mouse model provides a valuable tool to dissect the cellular mechanisms underlying SPTAN1 encephalopathies and could support the development of targeted therapies. However, further structural and functional analyses of R1098Q mutant mice are essential to fully elucidate the diverse pathological consequences of αII-spectrin dysfunction and to better define the spectrum of αII-spectrinopathies.