title: Nucleolar integrity is required for the maintenance of long-term synaptic plasticity.
abstract: Long-term memory (LTM) formation requires new protein synthesis and new gene expression. Based on our work in Aplysia, we hypothesized that the rRNA genes, stimulation-dependent targets of the enzyme Poly(ADP-ribose) polymerase-1 (PARP-1), are primary effectors of the activity-dependent changes in synaptic function that maintain synaptic plasticity and memory. Using electrophysiology, immunohistochemistry, pharmacology and molecular biology techniques, we show here, for the first time, that the maintenance of forskolin-induced late-phase long-term potentiation (L-LTP) in mouse hippocampal slices requires nucleolar integrity and the expression of new rRNAs. The activity-dependent upregulation of rRNA, as well as L-LTP expression, are poly(ADP-ribosyl)ation (PAR) dependent and accompanied by an increase in nuclear PARP-1 and Poly(ADP) ribose molecules (pADPr) after forskolin stimulation. The upregulation of PARP-1 and pADPr is regulated by Protein kinase A (PKA) and extracellular signal-regulated kinase (ERK)--two kinases strongly associated with long-term plasticity and learning and memory. Selective inhibition of RNA Polymerase I (Pol I), responsible for the synthesis of precursor rRNA, results in the segmentation of nucleoli, the exclusion of PARP-1 from functional nucleolar compartments and disrupted L-LTP maintenance. Taken as a whole, these results suggest that new rRNAs (28S, 18S, and 5.8S ribosomal components)--hence, new ribosomes and nucleoli integrity--are required for the maintenance of long-term synaptic plasticity. This provides a mechanistic link between stimulation-dependent gene expression and the new protein synthesis known to be required for memory consolidation.
authors.affiliation: Department of Pathology, State University of New York, Downstate Medical Center, Brooklyn, New York, United States of America; Department of Biology, School of Science, Health and Technology, City University of New York, Medgar Evers College, Brooklyn, New York, United States of America.
authors.forename: Kim D
authors.initials: KD
authors.lastname: Allen
authors.affiliation: Department of Pathology, State University of New York, Downstate Medical Center, Brooklyn, New York, United States of America.
authors.forename: Andrei V
authors.initials: AV
authors.lastname: Gourov
authors.affiliation: Department of Pathology, State University of New York, Downstate Medical Center, Brooklyn, New York, United States of America.
authors.forename: Christopher
authors.initials: C
authors.lastname: Harte
authors.affiliation: Department of Pathology, State University of New York, Downstate Medical Center, Brooklyn, New York, United States of America.
authors.forename: Peng
authors.initials: P
authors.lastname: Gao
authors.affiliation: Department of Pathology, State University of New York, Downstate Medical Center, Brooklyn, New York, United States of America.
authors.forename: Clarice
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Pathology, State University of New York, Downstate Medical Center, Brooklyn, New York, United States of America.
authors.forename: Darlene
authors.initials: D
authors.lastname: Sylvain
authors.affiliation: Department of Pathology, State University of New York, Downstate Medical Center, Brooklyn, New York, United States of America.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Splett
authors.affiliation: Department of Pathology, State University of New York, Downstate Medical Center, Brooklyn, New York, United States of America; The Robert F. Furchgott Center for Neural and Behavioral Science, State University of New York, Downstate Medical Center, Brooklyn, New York, United States of America.
authors.forename: William C
authors.initials: WC
authors.lastname: Oxberry
authors.affiliation: Departments of Physiology and Pharmacology, State University of New York, Downstate Medical Center, Brooklyn, New York, United States of America.
authors.forename: Paula S
authors.initials: PS
authors.lastname: van de Nes
authors.affiliation: Departments of Physiology and Pharmacology, State University of New York, Downstate Medical Center, Brooklyn, New York, United States of America.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Troy-Regier
authors.affiliation: Department of Pathology, State University of New York, Downstate Medical Center, Brooklyn, New York, United States of America.
authors.forename: Jason
authors.initials: J
authors.lastname: Wolk
authors.affiliation: Department of Pathology, State University of New York, Downstate Medical Center, Brooklyn, New York, United States of America; The Robert F. Furchgott Center for Neural and Behavioral Science, State University of New York, Downstate Medical Center, Brooklyn, New York, United States of America.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Alarcon
authors.affiliation: Department of Pathology, State University of New York, Downstate Medical Center, Brooklyn, New York, United States of America; The Robert F. Furchgott Center for Neural and Behavioral Science, State University of New York, Downstate Medical Center, Brooklyn, New York, United States of America.
authors.forename: A Iván
authors.initials: AI
authors.lastname: Hernández
mesh_terms: D000818:Animals; D005576:Colforsin / Q000008:administration & dosage; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D057567:Memory, Long-Term / Q000502:physiology*; D051379:Mice; D009473:Neuronal Plasticity / Q000235:genetics* / Q000502:physiology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011064:Poly Adenosine Diphosphate Ribose / Q000096:biosynthesis / Q000235:genetics; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis* / Q000235:genetics; D012339:RNA, Ribosomal, 28S / Q000096:biosynthesis / Q000235:genetics; D013569:Synapses / Q000235:genetics* / Q000502:physiology
chemical_list: D012339:RNA, Ribosomal, 28S; D005576:Colforsin; D011064:Poly Adenosine Diphosphate Ribose; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D017868:Cyclic AMP-Dependent Protein Kinases
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