Critical roles of [alpha]II spectrin in brain development and epileptic encephalopathy

The nonerythrocytic [alpha]-spectrin-1 (SPTAN1) gene encodes the cytoskeletal protein [alpha]II spectrin. Mutations in SPTAN1 cause early infantile epileptic encephalopathy type 5 (EIEE5); however, the role of [alpha]II spectrin in neurodevelopment and EIEE5 pathogenesis is unknown. Prior work suggests that [alpha]II spectrin is absent in the axon initial segment (AIS) and contributes to a diffusion barrier in the distal axon. Here, we have shown that [alpha]II spectrin is expressed ubiquitously in rodent and human somatodendritic and axonal domains. CRISPR-mediated deletion of Sptan1 in embryonic rat forebrain by in utero electroporation caused altered dendritic and axonal development, loss of the AIS, and decreased inhibitory innervation. Overexpression of human EIEE5 mutant SPTAN1 in embryonic rat forebrain and mouse hippocampal neurons led to similar developmental defects that were also observed in EIEE5 patient-derived neurons. Additionally, patient-derived neurons displayed aggregation of spectrin complexes. Taken together, these findings implicate [alpha]II spectrin in critical aspects of dendritic and axonal development and synaptogenesis, and support a dominant-negative mechanism of SPTAN1 mutations in EIEE5.
Introduction Early infantile epileptic encephalopathies (EIEEs) are a devastating group of epilepsies characterized by refractory seizures and cognitive arrest or regression, and they typically carry a poor prognosis (1). Recent [...]