Abstract
Homeostatic synaptic scaling calibrates neuronal excitability by adjusting synaptic strengths during prolonged changes in synaptic activity. The molecular mechanisms that regulate the trafficking of AMPA receptors (AMPARs) during synaptic scaling are largely unknown. Here, we show that chronic activity blockade reduces PICK1 protein level on a time scale that coincides with the accumulation of surface AMPARs. PICK1 loss of function alters the subunit composition and the abundance of GluA2-containing AMPARs. Due to aberrant trafficking of these receptors, the increase in synaptic strength in response to synaptic inactivity is occluded in neurons generated from PICK1 knock-out mouse. In agreement with electrophysiological recordings, no defect of AMPAR trafficking is observed in PICK1 knock-out neurons in response to elevated neuronal activity. Overall, our data reveal an important role of PICK1 in inactivity-induced synaptic scaling by regulating the subunit composition, abundance, and trafficking of GluA2-containing AMPARs.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bicuculline / pharmacology
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Biotinylation / methods
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Carrier Proteins / metabolism
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Cell Cycle Proteins
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Cells, Cultured
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Cerebral Cortex / cytology
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Embryo, Mammalian
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Excitatory Postsynaptic Potentials / drug effects
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Excitatory Postsynaptic Potentials / genetics
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GABA-A Receptor Antagonists / pharmacology
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Green Fluorescent Proteins / genetics
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Homeostasis / drug effects
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Homeostasis / physiology*
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Humans
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neuronal Plasticity
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Neurons / cytology*
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Neurons / drug effects
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Nuclear Proteins / deficiency*
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Nuclear Proteins / metabolism
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Protein Subunits / genetics
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Protein Subunits / metabolism
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Protein Transport / drug effects
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Protein Transport / genetics
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RNA, Small Interfering / pharmacology
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Receptors, AMPA / genetics
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Receptors, AMPA / metabolism
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Sodium Channel Blockers / pharmacology
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Statistics, Nonparametric
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Synapses / drug effects
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Synapses / metabolism*
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Tetrodotoxin / pharmacology
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Transfection / methods
Substances
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Carrier Proteins
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Cell Cycle Proteins
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GABA-A Receptor Antagonists
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Nuclear Proteins
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Prkcabp protein, mouse
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Protein Subunits
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RNA, Small Interfering
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Receptors, AMPA
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Sodium Channel Blockers
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Green Fluorescent Proteins
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Tetrodotoxin
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Bicuculline