Abstract
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.
Copyright © 2016 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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A Kinase Anchor Proteins / genetics
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A Kinase Anchor Proteins / metabolism*
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Animals
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Calcineurin / genetics
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Calcineurin / metabolism*
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Calcium / metabolism*
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Cyclic AMP-Dependent Protein Kinases / genetics
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Cyclic AMP-Dependent Protein Kinases / metabolism*
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Electric Stimulation
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Enzyme Inhibitors / pharmacology
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Excitatory Amino Acid Agents / pharmacology
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Hippocampus / cytology
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Hippocampus / ultrastructure
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Long-Term Synaptic Depression / drug effects
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Long-Term Synaptic Depression / genetics
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Long-Term Synaptic Depression / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Models, Molecular
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Mutation / genetics
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Receptors, AMPA / genetics
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Receptors, AMPA / metabolism*
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Receptors, N-Methyl-D-Aspartate / genetics
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Receptors, N-Methyl-D-Aspartate / metabolism*
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Silver Staining
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Synapses / genetics
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Synapses / physiology*
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Synapses / ultrastructure
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Synaptic Potentials / drug effects
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Synaptic Potentials / genetics
Substances
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A Kinase Anchor Proteins
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Akap5 protein, mouse
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Enzyme Inhibitors
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Excitatory Amino Acid Agents
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Receptors, AMPA
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Receptors, N-Methyl-D-Aspartate
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Cyclic AMP-Dependent Protein Kinases
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Calcineurin
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Calcium