The Molecular Motor KIF21B Mediates Synaptic Plasticity and Fear Extinction by Terminating Rac1 Activation

Fear extinction is a component of cognitive flexibility that is relevant for important psychiatric diseases, but its molecular mechanism is still largely elusive. We established mice lacking the kinesin-4 motor KIF21B as a model for fear extinction defects. Postsynaptic NMDAR-dependent long-term depression (LTD) is specifically impaired in knockouts. NMDAR-mediated LTD-causing stimuli induce dynamic association of KIF21B with the Rac1GEF subunit engulfment and cell motility protein 1 (ELMO1), leading to ELMO1 translocation out of dendritic spines and its sequestration in endosomes. This process may essentially terminate transient activation of Rac1, shrink spines, facilitate AMPAR endocytosis, and reduce postsynaptic strength, thereby forming a mechanistic link to LTD expression. Antagonizing ELMO1/Dock Rac1GEF activity by the administration of 4-[3′-(2″-chlorophenyl)-2′-propen-1′-ylidene]-1-phenyl-3,5-pyrazolidinedione (CPYPP) significantly reverses the knockout phenotype. Therefore, we propose that KIF21B-mediated Rac1 inactivation is a key molecular event in NMDAR-dependent LTD expression underlying cognitive flexibility in fear extinction. [Display omitted] •The KIF21B-knockout mouse lacks cognitive flexibility including fear extinction•NMDAR-LTD involves a KIF21B-dependent Rac1 activity cycle in dendritic spines•KIF21B sequesters ELMO1 Rac1GEF from dendritic spines to shaft endosomes•The ELMO1 Rac1GEF antagonist CPYPP reverses the phenotype in vivo and in vitro Morikawa et al. establish a mouse model lacking NMDAR-mediated cognitive flexibility by deleting the Kif21b kinesin gene. The mouse is impaired in terminating a Rac1 activity cycle by ELMO1 sequestration for LTD expression and treatable by the Rac1GEF inhibitor CPYPP. These findings have implications for further study of cognitive flexibility.