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

Momo Morikawa1, Yosuke Tanaka1, Hyun-Soo Cho1

  • 1Department of Cell Biology and Anatomy, Graduate School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.

Cell Reports
|June 28, 2018
PubMed

Insights

Kinesin-4 motor KIF21B deficiency impairs fear extinction by disrupting NMDAR-dependent long-term depression (LTD). KIF21B inactivation of Rac1 is crucial for LTD expression and cognitive flexibility.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cognitive Science

Background:

  • Fear extinction, a key aspect of cognitive flexibility, is vital for mental health but its molecular underpinnings remain unclear.
  • Deficits in fear extinction are implicated in psychiatric disorders, highlighting the need for mechanistic understanding.

Purpose of the Study:

  • To elucidate the molecular mechanisms governing fear extinction.
  • To investigate the role of the kinesin-4 motor KIF21B in synaptic plasticity and cognitive flexibility.

Main Methods:

  • Generation of KIF21B knockout mice to model fear extinction defects.
  • Electrophysiological analysis of NMDAR-dependent long-term depression (LTD) in knockout mice.
  • Investigation of KIF21B and ELMO1 interaction dynamics during LTD induction.
  • Pharmacological intervention using CPYPP to antagonize ELMO1/Dock Rac1GEF activity.

Main Results:

  • KIF21B knockout mice exhibit specific impairments in postsynaptic NMDAR-dependent LTD.
  • NMDAR-mediated LTD induces KIF21B-ELMO1 association, leading to ELMO1 sequestration and Rac1 inactivation.
  • This process involves dendritic spine shrinkage and reduced postsynaptic strength, linking KIF21B to LTD.
  • Administration of CPYPP significantly reverses the fear extinction phenotype in knockout mice.

Conclusions:

  • KIF21B plays a critical role in NMDAR-dependent LTD expression.
  • KIF21B-mediated Rac1 inactivation is a key molecular event underlying cognitive flexibility in fear extinction.
  • Targeting the KIF21B-ELMO1 pathway offers potential therapeutic strategies for fear extinction deficits.
Keywords:
CPYPPELMO1KIF21BLTDNMDAR-mediated LTDRac1 activity cyclecognitive flexibilityfear extinctionkinesinsynaptic plasticity

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