The phosphorylation and SUMOylation of spastin modulate AMPAR GluA2 subunits trafficking in hippocampal neurons

Point mutations in SPG4,the gene encoding spastin,are a frequent cause of hereditary spastic paraplegia(HSP).In some complex HSP cases,there is cognitive impairment.Dynamic trafficking of AMPA receptors into and out of synapses is a key determinant of synaptic plasticity and further implicates learning and memory.However,the exact molecular mechanisms underlying AMPARs trafficking still remains unclear.Here,we performed immunofluorescence staining,whole-cell patch clamp,GST pull-down,and CoIP assays.First,we found that the desumoylation mutant at 427-site of spastin lost its microtubule severing function.Second,our results revealed the maturation of dendritic spines and the increase of GluA2 membrane trafficking after overexpression de-SUMO spastin in cultured hippocampal neurons.Also,we found that the interaction between de SUMO spastin and the GluA2 subunits increased in vitro and in vivo,which were enhanced by the 210-site phosphorylation of spastin at the mean time.Similarly,the phosphorylation modifications enhanced the maturation of dendritic spines and the increasing membrane GluA2 caused by de SUMO spastin.Thus,we show the reciprocal regulation between the phosphorylation and sumoylation of spastin,and jointly modulate the AMPA receptor GluA2 subunits trafficking in cultured hippocampal neurons.