Regulation of NMDA receptor trafficking is crucial to modulate neuronal communication. Ca 2+/calmodulin-dependent protein kinase phosphorylates the tail domain of KIF17, a member of the kinesin superfamily, to controlNMDAreceptor subunit 2B (GluN2B) transport by changing the KIF17-cargo interaction in vitro. However, the mechanisms of regulation of GluN2B transport in vivo and its physiological significance are unknown. We generated transgenic mice carrying wild-type KIF17 (TgS), or KIF17 with S1029A (TgA) or S1029D (TgD) phosphomimic mutations in kif17 -/- background. TgA/kif17 -/- and TgD/kif17 -/- mice exhibited reductions in synaptic NMDA receptors because of their inability to load/unload GluN2B onto/from KIF17, leading to impaired neuronal plasticity, CREB activation, and spatial memory. Expression of GFP-KIF17 in TgS/kif17 -/- mouse neurons rescued the synaptic and behavioral defects of kif17 -/- mice. These results suggest that phosphorylation-based regulation of NMDA receptor transport is critical for learning and memory in vivo.
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