An activity-dependent local transport regulation via degradation and synthesis of KIF17 underlying cognitive flexibility.

Synaptic weight changes among postsynaptic densities within a single dendrite are regulated by the balance between localized protein degradation and synthesis. However, the molecular mechanism via these opposing regulatory processes is still elusive. Here, we showed that the molecular motor KIF17 was locally degraded and synthesized in an N-methyl-d-aspartate receptor (NMDAR)-mediated activity-dependent manner. Accompanied by the degradation of KIF17, its transport was temporarily dampened in dendrites. We also observed that activity-dependent local KIF17 synthesis driven by its 3' untranslated region (3'UTR) occurred at dendritic shafts, and the newly synthesized KIF17 moved along the dendrites. Furthermore, hippocampus-specific deletion of Kif17 3'UTR disrupted KIF17 synthesis induced by fear memory retrieval, leading to impairment in extinction of fear memory. These results indicate that the regulation of the KIF17 transport is driven by the single dendrite-restricted cycle of degradation and synthesis that underlies cognitive flexibility.