title: Arc in the nucleus regulates PML-dependent GluA1 transcription and homeostatic plasticity.
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.
authors.affiliation: Gladstone Institutes of Neurological Disease, San Francisco, California, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Korb
authors.forename: Carol L
authors.initials: CL
authors.lastname: Wilkinson
authors.forename: Ryan N
authors.initials: RN
authors.lastname: Delgado
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Lovero
authors.forename: Steven
authors.initials: S
authors.lastname: Finkbeiner
mesh_terms: D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D001921:Brain / Q000166:cytology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D004622:Embryo, Mammalian; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000235:genetics; D051528:Guanylate Kinases / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure; D019913:Nuclear Localization Signals / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D018091:Receptors, AMPA / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D001640:Bicuculline; D003598:Cytoskeletal Proteins; D000076122:Disks Large Homolog 4 Protein; D058787:GABA-A Receptor Antagonists; D051528:Guanylate Kinases; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D019913:Nuclear Localization Signals; D016760:Proto-Oncogene Proteins c-fos; D018091:Receptors, AMPA; D013779:Tetrodotoxin; D001616:beta-Galactosidase; C501447:Dlg4 protein, mouse; C092069:activity regulated cytoskeletal-associated protein