Abstract
The activity-regulated cytoskeletal protein Arc (also known as Arg3.1) is required for long-term memory formation and synaptic plasticity. Arc expression is robustly induced by activity, and Arc protein localizes to both active synapses and the nucleus. Whereas its synaptic function has been examined, it is not clear why or how Arc is localized to the nucleus. We found that murine Arc nuclear expression is regulated by synaptic activity in vivo and in vitro. We identified distinct regions of Arc that control its localization, including a nuclear localization signal, a nuclear retention domain and a nuclear export signal. Arc localization to the nucleus promotes an activity-induced increase in the expression of promyelocytic leukemia nuclear bodies, which decreases GluA1 (also called Gria1) transcription and synaptic strength. We further show that Arc nuclear localization regulates homeostatic plasticity. Thus, Arc mediates the homeostatic response to increased activity by translocating to the nucleus, increasing promyelocytic leukemia protein expression and decreasing GluA1 transcription, ultimately downscaling synaptic strength.
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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Brain / cytology
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism*
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism*
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Disks Large Homolog 4 Protein
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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 / genetics
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Guanylate Kinases / metabolism
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Homeostasis / drug effects
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Homeostasis / genetics
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Homeostasis / physiology*
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Male
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Mutation / genetics
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Neuronal Plasticity / drug effects
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Neuronal Plasticity / physiology*
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Neurons / drug effects
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Neurons / ultrastructure
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Nuclear Localization Signals / genetics
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Nuclear Localization Signals / metabolism
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Protein Transport / drug effects
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Protein Transport / genetics
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Proto-Oncogene Proteins c-fos / metabolism
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Rats
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Rats, Long-Evans
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Receptors, AMPA / metabolism*
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Tetrodotoxin / pharmacology
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beta-Galactosidase / genetics
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beta-Galactosidase / metabolism
Substances
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Cytoskeletal Proteins
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Disks Large Homolog 4 Protein
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Dlg4 protein, mouse
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GABA-A Receptor Antagonists
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Membrane Proteins
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Nerve Tissue Proteins
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Nuclear Localization Signals
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Proto-Oncogene Proteins c-fos
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Receptors, AMPA
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activity regulated cytoskeletal-associated protein
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Tetrodotoxin
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Guanylate Kinases
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beta-Galactosidase
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glutamate receptor ionotropic, AMPA 1
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Bicuculline