Molecular motor KIF17 is fundamental for memory and learning via differential support of synaptic NR2A/2B levels

Neuron. 2011 Apr 28;70(2):310-25. doi: 10.1016/j.neuron.2011.02.049.

Abstract

Kinesin superfamily motor protein 17 (KIF17) is a candidate transporter of N-methyl-D-aspartate (NMDA) receptor subunit 2B (NR2B). Disruption of the murine kif17 gene inhibits NR2B transport, accompanied by decreased transcription of nr2b, resulting in a loss of synaptic NR2B. In kif17(-/-) hippocampal neurons, the NR2A level is also decreased because of accelerated ubiquitin-proteasome system-dependent degradation. Accordingly, NMDA receptor-mediated synaptic currents, early and late long-term potentiation, long-term depression, and CREB responses are attenuated in kif17(-/-) neurons, concomitant with a hippocampus-dependent memory impairment in knockout mice. In wild-type neurons, CREB is activated by synaptic inputs, which increase the levels of KIF17 and NR2B. Thus, KIF17 differentially maintains the levels of NR2A and NR2B, and, when synapses are stimulated, the NR2B/KIF17 complex is upregulated on demand through CREB activity. These KIF17-based mechanisms for maintaining NR2A/2B levels could underlie multiple phases of memory processes in vivo.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Analysis of Variance
  • Animals
  • Behavior, Animal
  • Biophysics / methods
  • Biotinylation
  • CREB-Binding Protein / metabolism
  • Cell Line, Transformed
  • Cell Movement / genetics
  • Cells, Cultured
  • Cycloheximide / pharmacology
  • Down-Regulation / genetics
  • Electric Stimulation / methods
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Agents / pharmacology
  • Excitatory Postsynaptic Potentials / genetics
  • Excitatory Postsynaptic Potentials / physiology
  • Fear
  • Green Fluorescent Proteins / genetics
  • Hippocampus / metabolism
  • Humans
  • Immunoprecipitation / methods
  • In Vitro Techniques
  • Kinesins / deficiency
  • Kinesins / physiology*
  • Maze Learning / physiology*
  • Mice
  • Mice, Transgenic
  • Neurons / drug effects
  • Neurons / physiology
  • Patch-Clamp Techniques
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Synthesis Inhibitors / pharmacology
  • Protein Transport / genetics
  • RNA, Messenger / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Recognition, Psychology / physiology*
  • Synaptophysin / metabolism
  • Time Factors
  • Time-Lapse Imaging / methods
  • Transfection
  • Ubiquitin / metabolism

Substances

  • Enzyme Inhibitors
  • Excitatory Amino Acid Agents
  • KIF17 protein, mouse
  • NR2A NMDA receptor
  • NR2B NMDA receptor
  • Protein Synthesis Inhibitors
  • RNA, Messenger
  • Receptors, N-Methyl-D-Aspartate
  • Synaptophysin
  • Ubiquitin
  • Green Fluorescent Proteins
  • Cycloheximide
  • CREB-Binding Protein
  • Proteasome Endopeptidase Complex
  • Kinesins