An essential role for PICK1 in NMDA receptor-dependent bidirectional synaptic plasticity

Neuron. 2008 Mar 27;57(6):872-82. doi: 10.1016/j.neuron.2008.01.028.

Abstract

PICK1 is a calcium-sensing, PDZ domain-containing protein that interacts with GluR2 and GluR3 AMPA receptor (AMPAR) subunits and regulates their trafficking. Although PICK1 has been principally implicated in long-term depression (LTD), PICK1 overexpression in CA1 pyramidal neurons causes a CaMK- and PKC-dependent potentiation of AMPAR-mediated transmission and an increase in synaptic GluR2-lacking AMPARs, mechanisms associated with NMDA receptor (NMDAR)-dependent long-term potentiation (LTP). Here, we directly tested whether PICK1 participates in both hippocampal NMDAR-dependent LTP and LTD. We show that the PICK1 potentiation of AMPAR-mediated transmission is NMDAR dependent and fully occludes LTP. Conversely, blockade of PICK1 PDZ interactions or lack of PICK1 prevents LTP. These observations demonstrate an important role for PICK1 in LTP. In addition, deletion of PICK1 or blockade of PICK1 PDZ binding prevented NMDAR-dependent LTD. Thus, PICK1 plays a critical role in bidirectional NMDAR-dependent long-term synaptic plasticity in the hippocampus.

Publication types

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

MeSH terms

  • 2-Amino-5-phosphonovalerate / pharmacology
  • Animals
  • Animals, Newborn
  • Carrier Proteins / metabolism*
  • Cytoskeletal Proteins
  • Excitatory Amino Acid Antagonists / pharmacology
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / physiology
  • Green Fluorescent Proteins / biosynthesis
  • Hippocampus / cytology
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / physiology*
  • Long-Term Potentiation / radiation effects
  • Long-Term Synaptic Depression / physiology*
  • Mice
  • Mice, Knockout
  • Nuclear Proteins / metabolism*
  • Patch-Clamp Techniques / methods
  • Peptides / pharmacology
  • Pyramidal Cells / cytology
  • Receptors, AMPA / deficiency
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Synapses / drug effects
  • Synapses / physiology*
  • Synapses / radiation effects
  • Tissue Culture Techniques

Substances

  • Carrier Proteins
  • Cytoskeletal Proteins
  • Excitatory Amino Acid Antagonists
  • Nuclear Proteins
  • PICK1 protein, rat
  • Peptides
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Green Fluorescent Proteins
  • 2-Amino-5-phosphonovalerate
  • glutamate receptor ionotropic, AMPA 2