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.
Highlights
IntroductionMore than half a century has passed since it was first noted that Long-term memory (LTM) formation requires new protein synthesis [1] and new gene expression [2] (reviewed by [3])—ideas that transformed the field of learning and memory by propelling it into the arena of molecular genetics
More than half a century has passed since it was first noted that Long-term memory (LTM) formation requires new protein synthesis [1] and new gene expression [2]—ideas that transformed the field of learning and memory by propelling it into the arena of molecular genetics
In Aplysia, we found that PARP-1 is necessary for long-term facilitation (LTF), and that among the activitydependent genes upregulated by PARP-1 were ribosomal RNA genes [11]
Summary
More than half a century has passed since it was first noted that LTM formation requires new protein synthesis [1] and new gene expression [2] (reviewed by [3])—ideas that transformed the field of learning and memory by propelling it into the arena of molecular genetics. Persistent forms of synaptic plasticity such as long-term facilitation (LTF) in invertebrates and long-term potentiation (LTP) in mammals have provided valuable models for investigating the molecular mechanism that underlies memory formation, consolidation and maintenance [3,4]. Most efforts to understand experience-induced changes in neuronal gene expression have focused on the transcription products of RNA polymerase II (precursor mRNA, snRNA and microRNA). The identities of the gene products that are both necessary and sufficient to consolidate activity-dependent, longterm plastic changes have remained elusive
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