NMDA Receptor-Dependent LTD Requires Transient Synaptic Incorporation of Ca²⁺-Permeable AMPARs Mediated by AKAP150-Anchored PKA and Calcineurin

Neuron. 2016 Mar 2;89(5):1000-15. doi: 10.1016/j.neuron.2016.01.043.


Information processing in the brain requires multiple forms of synaptic plasticity that converge on regulation of NMDA and AMPA-type glutamate receptors (NMDAR, AMPAR), including long-term potentiation (LTP) and long-term depression (LTD) and homeostatic scaling. In some cases, LTP and homeostatic plasticity regulate synaptic AMPAR subunit composition to increase the contribution of Ca(2+)-permeable receptors (CP-AMPARs) containing GluA1 but lacking GluA2 subunits. Here, we show that PKA anchored to the scaffold protein AKAP150 regulates GluA1 phosphorylation and plays a novel role controlling CP-AMPAR synaptic incorporation during NMDAR-dependent LTD. Using knockin mice that are deficient in AKAP-anchoring of either PKA or the opposing phosphatase calcineurin, we found that CP-AMPARs are recruited to hippocampal synapses by anchored PKA during LTD induction but are then rapidly removed by anchored calcineurin. Importantly, blocking CP-AMPAR recruitment, removal, or activity interferes with LTD. Thus, CP-AMPAR synaptic recruitment is required to transiently augment NMDAR Ca(2+) signaling during LTD induction.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • A Kinase Anchor Proteins / genetics
  • A Kinase Anchor Proteins / metabolism*
  • Animals
  • Calcineurin / genetics
  • Calcineurin / metabolism*
  • Calcium / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Electric Stimulation
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Agents / pharmacology
  • Hippocampus / cytology
  • Hippocampus / ultrastructure
  • Long-Term Synaptic Depression / drug effects
  • Long-Term Synaptic Depression / genetics
  • Long-Term Synaptic Depression / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Models, Molecular
  • Mutation / genetics
  • Receptors, AMPA / genetics
  • Receptors, AMPA / metabolism*
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Silver Staining
  • Synapses / genetics
  • Synapses / physiology*
  • Synapses / ultrastructure
  • Synaptic Potentials / drug effects
  • Synaptic Potentials / genetics


  • A Kinase Anchor Proteins
  • Akap5 protein, mouse
  • Enzyme Inhibitors
  • Excitatory Amino Acid Agents
  • Receptors, AMPA
  • Receptors, N-Methyl-D-Aspartate
  • Cyclic AMP-Dependent Protein Kinases
  • Calcineurin
  • Calcium