Nucleolar integrity is required for the maintenance of long-term synaptic plasticity

• Published in: PloS one Vol. 9; no. 8; p. e104364
• Main Authors: Allen, Kim D, Gourov, Andrei V, Harte, Christopher, Gao, Peng, Lee, Clarice, Sylvain, Darlene, Splett, Joshua M, Oxberry, William C, van de Nes, Paula S, Troy-Regier, Matthew J, Wolk, Jason, Alarcon, Juan M, Hernández, A Iván
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 04-08-2014; Public Library of Science (PLoS)
• Subjects: Adenosine diphosphate; ADP-ribosylation; Alzheimer's disease; Animals; Aplysia; Behavioral sciences; Biology and Life Sciences; Chemical synthesis; Colforsin - administration & dosage; Consolidation; Cyclic AMP-Dependent Protein Kinases - biosynthesis; Cyclic AMP-Dependent Protein Kinases - genetics; DNA-directed RNA polymerase; Electrophysiology; Enzymes; Epigenetics; Extracellular signal-regulated kinase; Forskolin; Furchgott, Robert F; Gene expression; Gene Expression - drug effects; Hippocampus; Hippocampus - drug effects; Hippocampus - physiology; Immunohistochemistry; Integrity; Kinases; Learning; Long term memory; Long-term potentiation; Long-Term Potentiation - drug effects; Long-Term Potentiation - genetics; Long-Term Potentiation - physiology; Maintenance; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - genetics; Memory; Memory, Long-Term - physiology; Mice; Molecular biology; Neuronal Plasticity - genetics; Neuronal Plasticity - physiology; Nucleoli; Pathology; Pharmacology; Physiology; Plasticity; Poly (ADP-Ribose) Polymerase-1; Poly Adenosine Diphosphate Ribose - biosynthesis; Poly Adenosine Diphosphate Ribose - genetics; Poly(ADP-ribose); Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerases - biosynthesis; Poly(ADP-ribose) Polymerases - genetics; Protein biosynthesis; Protein kinase A; Protein synthesis; Proteins; Ribonucleic acid; Ribose; Ribosomes; RNA; RNA, Ribosomal, 28S - biosynthesis; RNA, Ribosomal, 28S - genetics; rRNA; Segmentation; Stimulation; Synapses - genetics; Synapses - physiology; Synaptic plasticity; New York; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0104364

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.