Developmental changes in expression of βIV spectrin splice variants at axon initial segments and nodes of ranvier

Abstract

Axon initial segments (AIS) and nodes of Ranvier are highly specialized axonal membrane domains enriched in Na+ channels. These Na+ channel clusters play essential roles in action potential initiation and propagation. AIS and nodal Na+ channel complexes are linked to the actin cytoskeleton through βIV spectrin. However, neuronal βIV spectrin exists as two main splice variants: a longer βIVΣS1 variant with canonical N-terminal actin and aII spectrin-binding domains, and a shorter βIVΣS6 variant lacking these domains. Here, we show that the predominant neuronal βIV spectrin splice variant detected in the developing brain switches from bIVS1 to βIVΣS6, and that this switch is correlated with expression changes in ankyrinG (ankG) splice variants. We show that βIVΣS1 is the predominant splice variant at nascent and developing AIS and nodes of Ranvier, but with increasing age and in adults βIVΣS6 becomes the main splice variant. Remarkably, super-resolution microscopy revealed that the spacing of spectrin tetramers between actin rings remains unchanged, but that shorter spectrin tetramers may also be present. Thus, during development bIV spectrin may undergo a switch in the splice variants found at AIS and nodes of Ranvier.