Abstract
Homeostatic plasticity is crucial for maintaining neuronal output by counteracting unrestrained changes in synaptic strength. Chronic elevation of synaptic activity by bicuculline reduces the amplitude of miniature excitatory postsynaptic currents (mEPSCs), but the underlying mechanisms of this effect remain unclear. We found that activation of EphA4 resulted in a decrease in synaptic and surface GluR1 and attenuated mEPSC amplitude through a degradation pathway that requires the ubiquitin proteasome system (UPS). Elevated synaptic activity resulted in increased tyrosine phosphorylation of EphA4, which associated with the ubiquitin ligase anaphase-promoting complex (APC) and its activator Cdh1 in neurons in a ligand-dependent manner. APC(Cdh1) interacted with and targeted GluR1 for proteasomal degradation in vitro, whereas depletion of Cdh1 in neurons abolished the EphA4-dependent downregulation of GluR1. Knockdown of EphA4 or Cdh1 prevented the reduction in mEPSC amplitude in neurons that was a result of chronic elevated activity. Our results define a mechanism by which EphA4 regulates homeostatic plasticity through an APC(Cdh1)-dependent degradation pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Analysis of Variance
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Anaphase-Promoting Complex-Cyclosome
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Animals
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Bicuculline / pharmacology
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Cells, Cultured
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Down-Regulation / drug effects
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Down-Regulation / physiology*
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Electrophysiology
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Excitatory Postsynaptic Potentials / drug effects
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Excitatory Postsynaptic Potentials / physiology
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GABA-A Receptor Antagonists / pharmacology
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Hippocampus / cytology
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Hippocampus / drug effects
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Hippocampus / physiology
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Miniature Postsynaptic Potentials / drug effects
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Miniature Postsynaptic Potentials / physiology
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Neuronal Plasticity / drug effects
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Neuronal Plasticity / physiology*
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Neurons / cytology
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Neurons / drug effects
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Neurons / physiology*
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Proteasome Endopeptidase Complex / genetics
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Proteasome Endopeptidase Complex / metabolism
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RNA, Small Interfering
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Receptor, EphA4 / metabolism*
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Receptors, AMPA / genetics
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Receptors, AMPA / metabolism*
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Statistics, Nonparametric
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Synapses / drug effects
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Synapses / physiology
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Ubiquitin-Protein Ligase Complexes / genetics
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Ubiquitin-Protein Ligase Complexes / metabolism*
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Ubiquitination / drug effects
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Ubiquitination / physiology
Substances
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GABA-A Receptor Antagonists
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RNA, Small Interfering
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Receptors, AMPA
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Ubiquitin-Protein Ligase Complexes
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Anaphase-Promoting Complex-Cyclosome
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Receptor, EphA4
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Proteasome Endopeptidase Complex
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Bicuculline