The Retromer Supports AMPA Receptor Trafficking During LTP

Neuron. 2017 Apr 5;94(1):74-82.e5. doi: 10.1016/j.neuron.2017.03.020.

Abstract

Alterations in the function of the retromer, a multisubunit protein complex that plays a specialized role in endosomal sorting, have been linked to Alzheimer's and Parkinson's diseases, yet little is known about the retromer's role in the mature brain. Using in vivo knockdown of the critical retromer component VPS35, we demonstrate a specific role for this endosomal sorting complex in the trafficking of AMPA receptors during NMDA-receptor-dependent LTP at mature hippocampal synapses. The impairment of LTP due to VPS35 knockdown was mechanistically independent of any role of the retromer in the production of Aβ from APP. Finally, we find surprising differences between Alzheimer's- and Parkinson's-disease-linked VPS35 mutations in supporting this pathway. These findings demonstrate a key role for the retromer in LTP and provide insights into how retromer malfunction in the mature brain may contribute to symptoms of common neurodegenerative diseases. VIDEO ABSTRACT.

Keywords: Alzheimer’s disease; Parkinson’s disease; amyloid beta (Aβ); long-term potentiation (LTP); retromer; synaptic plasticity.

Publication types

  • Video-Audio Media

MeSH terms

  • Alzheimer Disease / genetics*
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Endosomal Sorting Complexes Required for Transport / genetics
  • Gene Knockdown Techniques
  • Hippocampus / cytology
  • Hippocampus / metabolism*
  • Long-Term Potentiation / genetics*
  • Mice
  • Mice, Knockout
  • Mutation
  • Neurons / metabolism
  • Parkinson Disease / genetics*
  • Protein Transport / genetics*
  • Receptors, AMPA / metabolism*
  • Synapses / metabolism*
  • Vesicular Transport Proteins / genetics*

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Endosomal Sorting Complexes Required for Transport
  • Receptors, AMPA
  • Vesicular Transport Proteins
  • Vps35 protein, mouse