Spectrins form a submembranous cytoskeleton proposed to confer strength and flexibility to neurons and to participate in ion channel clustering at axon initial segments (AIS) and nodes of Ranvier. Neuronal spectrin cytoskeletons consist of diverse β subunits and αII spectrin. Although αII spectrin is found in neurons in both axonal and somatodendritic domains, using proteomics, biochemistry, and super-resolution microscopy we show that αII and βIV spectrin interact and form a periodic AIS cytoskeleton. To determine the role of spectrins in the nervous system, we generated Sptan1(f/f) mice for deletion of CNS αII spectrin. We analyzed αII spectrin-deficient mice of both sexes and found that loss of αII spectrin causes profound reductions in all β spectrins. αII spectrin-deficient mice die before one month of age, have disrupted AIS and many other neurological impairments including seizures, disrupted cortical lamination, and widespread neurodegeneration. These results demonstrate the importance of the spectrin cytoskeleton both at the AIS and throughout the nervous system.SIGNIFICANCE STATEMENTSpectrin cytoskeletons play diverse roles in neurons including assembly of excitable domains like the axon initial segment and nodes of Ranvier. However, the molecular composition and structure of these cytoskeletons remain poorly understood. Here, we show αII spectrin partners with βIV spectrin to form a periodic cytoskeleton at axon initial segments and nodes of Ranvier. Using a new αII spectrin conditional knockout mouse we show that αII spectrin is required for axon initial segment assembly, neuronal excitability, cortical lamination, and to protect against neurodegeneration. These results demonstrate the broad importance of spectrin cytoskeletons for nervous system function and development, and have important implications for nervous system injuries and diseases because disruption of the spectrin cytoskeleton is a common molecular pathology.
PMID: 29038240 [PubMed - as supplied by publisher]