Molecular motor protein KIF5C mediates structural plasticity and long-term memory by constraining local translation

Cell Rep. 2021 Jul 13;36(2):109369. doi: 10.1016/j.celrep.2021.109369.

Abstract

Synaptic structural plasticity, key to long-term memory storage, requires translation of localized RNAs delivered by long-distance transport from the neuronal cell body. Mechanisms and regulation of this system remain elusive. Here, we explore the roles of KIF5C and KIF3A, two members of kinesin superfamily of molecular motors (Kifs), and find that loss of function of either kinesin decreases dendritic arborization and spine density whereas gain of function of KIF5C enhances it. KIF5C function is a rate-determining component of local translation and is associated with ∼650 RNAs, including EIF3G, a regulator of translation initiation, and plasticity-associated RNAs. Loss of function of KIF5C in dorsal hippocampal CA1 neurons constrains both spatial and contextual fear memory, whereas gain of function specifically enhances spatial memory and extinction of contextual fear. KIF5C-mediated long-distance transport of local translation substrates proves a key mechanism underlying structural plasticity and memory.

Keywords: RNA transport; kinesin; learning and memory; local translation; molecular motor proteins; structural plasticity; synaptic transmission.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Dendritic Spines / metabolism
  • Excitatory Postsynaptic Potentials
  • Fear
  • Female
  • Gain of Function Mutation
  • HEK293 Cells
  • Hippocampus / metabolism
  • Humans
  • Kinesins / metabolism*
  • Learning
  • Male
  • Memory Disorders / metabolism
  • Memory Disorders / pathology
  • Memory Disorders / physiopathology
  • Memory, Long-Term*
  • Mice
  • Mice, Inbred C57BL
  • Molecular Motor Proteins / metabolism*
  • Neuronal Plasticity*
  • Protein Biosynthesis*
  • RNA Transport
  • Signal Transduction
  • Synapses / metabolism
  • Synaptic Transmission

Substances

  • Kif3a protein, mouse
  • Molecular Motor Proteins
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • KIF5C protein, mouse
  • Kinesins