PKM zeta maintains late long-term potentiation by N-ethylmaleimide-sensitive factor/GluR2-dependent trafficking of postsynaptic AMPA receptors

J Neurosci. 2008 Jul 30;28(31):7820-7. doi: 10.1523/JNEUROSCI.0223-08.2008.

Abstract

Although the maintenance mechanism of late long-term potentiation (LTP) is critical for the storage of long-term memory, the expression mechanism of synaptic enhancement during late-LTP is unknown. The autonomously active protein kinase C isoform, protein kinase Mzeta (PKMzeta), is a core molecule maintaining late-LTP. Here we show that PKMzeta maintains late-LTP through persistent N-ethylmaleimide-sensitive factor (NSF)/glutamate receptor subunit 2 (GluR2)-dependent trafficking of AMPA receptors (AMPARs) to the synapse. Intracellular perfusion of PKMzeta into CA1 pyramidal cells causes potentiation of postsynaptic AMPAR responses; this synaptic enhancement is mediated through NSF/GluR2 interactions but not vesicle-associated membrane protein-dependent exocytosis. PKMzeta may act through NSF to release GluR2-containing receptors from a reserve pool held at extrasynaptic sites by protein interacting with C-kinase 1 (PICK1), because disrupting GluR2/PICK1 interactions mimic and occlude PKMzeta-mediated AMPAR potentiation. During LTP maintenance, PKMzeta directs AMPAR trafficking, as measured by NSF/GluR2-dependent increases of GluR2/3-containing receptors in synaptosomal fractions from tetanized slices. Blocking this trafficking mechanism reverses established late-LTP and persistent potentiation at synapses that have undergone synaptic tagging and capture. Thus, PKMzeta maintains late-LTP by persistently modifying NSF/GluR2-dependent AMPAR trafficking to favor receptor insertion into postsynaptic sites.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Excitatory Postsynaptic Potentials / physiology*
  • Isoenzymes / physiology
  • Long-Term Potentiation / physiology*
  • Male
  • Molecular Sequence Data
  • N-Ethylmaleimide-Sensitive Proteins / physiology*
  • Protein Kinase C / physiology*
  • Protein Transport / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Receptors, AMPA / metabolism
  • Receptors, AMPA / physiology*

Substances

  • Isoenzymes
  • Receptors, AMPA
  • Protein Kinase C
  • protein kinase M zeta, rat
  • N-Ethylmaleimide-Sensitive Proteins
  • glutamate receptor ionotropic, AMPA 2