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Core fucosylation is catalyzed by1,6-fucosyltransferase (FUT8), which transfers a fucose residue to the innermost GlcNAc residue via α1,6-linkage on N-glycans in mammals. We previously reported that Fut8-knock-out (Fut8-/-) mice showed a schizophrenia-like phenotype and a decrease in work- ing memory. To understand the underlying molecular mechanism, we analyzed early form long term potentiation (E-LTP), which is closely related to learning and memory in the hippocampus. The scale of E-LTP induced by high frequency stimulation was significantly decreased in Fut8-/- mice. Tetraethylammonium-induced LTP showed no significant differences, suggesting that the decline in E-LTPwas caused by postsynaptic events. Unexpectedly, the phosphorylation levels of calcium/ calmodulin-dependent protein kinase II (CaMKII), an important mediator of learning and memory in postsynapses, were/ greatly increased in Fut8-/- mice. The expression levels of-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs) in the postsynaptic density were enhanced in/ Fut8-/- mice, although there were no significant differences in the total expression levels, implicating that AMPARs without core fucosylationmight exist in an active state. The activation of AMPARs was further confirmed by Fura-2 calcium imaging using primary cultured neurons. Taken together, loss of core fucosylation on AMPARs enhanced their heteromerization, which increase sensitivity for postsynaptic depolarization and persistently activate N-methyl-D-aspartate receptors as well as Ca2+ influx and CaMKII and then impair LTP. [ABSTRACT FROM AUTHOR]