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.

RNA polymerase I transcription is modulated by spatial learning in different brain regions

“…It has to be noticed that similar conclusions have also been reached through in vitro experiments (Allen et al . ). Interestingly, previous studies demonstrated that mRNAs coding for ribosomal proteins are present at synapses (Moccia et al .…”

“…This observation is in line with a recent study (Allen et al . ) demonstrating that the blockade of rRNA transcription in vitro impairs the long‐term potentiation of hippocampal synapses, a process known to share several molecular commonalities with memory formation (Morris et al . ; Giese et al .…”

“…Recently, the need for rRNA synthesis has been demonstrated for LTP (long‐term potentiation) (Allen et al . ), which is generally considered a good cellular correlate of memory (Izquierdo and Medina ). However, while the role of protein synthesis in memory has been intensely investigated, the relationship between rRNA transcription and memory formation has been hardly explored.…”

RNA Polymerase 1 Is Transiently Regulated by Seizures and Plays a Role in a Pharmacological Kindling Model of Epilepsy

“…In the hippocampus, induction of long term potentiation (LTP) or spatial learning is associated with increased Pol1 activity [22,23]. In addition, LTP is disrupted by genetic or pharmacological inhibition of hippocampal Pol1, while the latter manipulation also negatively effects spatial memory consolidation [24,23,22]. Importantly, these defects are unlikely to be due to neuronal death, as mature forebrain neurons survive for months without active Pol1 [25,24].…”

Ribosomal RNA – a tail wagging the dog?

“…The observation reported here of an increased rRNA transcription upon learning and the need of nucleolar integrity for the maintenance of LTM and LTP confirms nicely the earlier in vitro observations made in mouse hippocampal slices (Allen et al . ). However, methods used by Capitano and co‐workers (JNC, this issue) raise several additional questions, to be urgently addressed in order to elucidate the complex intra‐ and interneuronal molecular processes, associated with learning.…”