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

Cell Rep. 2018 Jun 26;23(13):3864-3877. doi: 10.1016/j.celrep.2018.05.089.

Abstract

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.

Keywords: CPYPP; ELMO1; KIF21B; LTD; NMDAR-mediated LTD; Rac1 activity cycle; cognitive flexibility; fear extinction; kinesin; synaptic plasticity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Dendritic Spines / metabolism
  • Endocytosis
  • Endosomes / metabolism
  • Fear / physiology*
  • Guanosine Triphosphate / metabolism
  • Kinesins / deficiency
  • Kinesins / genetics
  • Kinesins / metabolism*
  • Long-Term Synaptic Depression / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neuronal Plasticity* / drug effects
  • Neuropeptides / antagonists & inhibitors
  • Neuropeptides / metabolism*
  • Protein Binding
  • Protein Subunits / antagonists & inhibitors
  • Protein Subunits / metabolism
  • Pyrazoles / pharmacology
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • rac1 GTP-Binding Protein / antagonists & inhibitors
  • rac1 GTP-Binding Protein / metabolism*

Substances

  • 4-(3'-(2'-chlorophenyl)-2'-propen-1'-ylidene)-1-phenyl-3,5-pyrazolidinedione
  • Adaptor Proteins, Signal Transducing
  • ELMO1 protein, mouse
  • Kif21b protein, mouse
  • Neuropeptides
  • Protein Subunits
  • Pyrazoles
  • Rac1 protein, mouse
  • Receptors, N-Methyl-D-Aspartate
  • Guanosine Triphosphate
  • Kinesins
  • rac1 GTP-Binding Protein