Learning-induced ribosomal RNA is required for memory consolidation in mice—Evidence of differentially expressed rRNA variants in learning and memory

Kim D Allen,Panayiotis Tsokas,A Iván Hernández,Jason Wolk,Maya Barnard,Matthew J Regier,Shwetha Phatarpekar,André A Fenton,Changchi Hsieh,Todd C Sacktor,Michal Hetman

doi:10.1371/journal.pone.0203374

Abstract

The transition from short-term to long-term forms of synaptic plasticity requires protein synthesis and new gene expression. Most efforts to understand experience-induced changes in neuronal gene expression have focused on the transcription products of RNA polymerase II—primarily mRNAs and the proteins they encode. We recently showed that nucleolar integrity and activity-dependent ribosomal RNA (rRNA) synthesis are essential for the maintenance of hippocampal long-term potentiation (LTP). Consequently, the synaptic plasticity and memory hypothesis predicts that nucleolar integrity and activity dependent rRNA synthesis would be required for Long-term memory (LTM). We tested this prediction using the hippocampus-dependent, Active Place Avoidance (APA) spatial memory task and found that training induces de novo rRNA synthesis in mouse dorsal hippocampus. This learning-induced increase in nucleolar activity and rRNA synthesis persists at least 24 h after training. In addition, intra-hippocampal injection of the Pol I specific inhibitor, CX-5461 prior to training, revealed that de novo rRNA synthesis is required for 24 h memory, but not for learning. Using qPCR to assess activity-dependent changes in gene expression, we found that of seven known rRNA expression variants (v-rRNAs), only one, v-rRNA IV, is significantly upregulated right after training. These data indicate that learning induced v-rRNAs are crucial for LTM, and constitute the first evidence that differential rRNA gene expression plays a role in memory.

Highlights

In 1950, Katz and Halstead first proposed that memory formation required new protein synthesis) [1] —a hypothesis that was not tested until decades later [2,3,4]
We demonstrated in vitro that nucleolar integrity and the synthesis of new poly ADP ribose polymerase-1 (PARP-1) dependent ribosomal RNA (rRNA) are required for the maintenance of long-term synaptic plasticity [13, 15]
1-dependent activation of rRNA synthesis in the neuronal nucleolus. This activation has been shown to be necessary for late-phase long-term potentiation (LTP), an ex vivo model of memory [15]. These results led to the prediction that nucleolar integrity and activity-dependent rRNA synthesis would be required for Long-term memory (LTM), in vivo

Summary

Introduction

In 1950, Katz and Halstead first proposed that memory formation required new protein synthesis) [1] —a hypothesis that was not tested until decades later [2,3,4]. It is well accepted that memory consolidation requires new transcription and new activity-dependent protein synthesis [5, 6]. Most efforts to understand experience-induced changes in neuronal gene expression have focused on the transcription products of RNA polymerase II (Pol II)—primarily mRNAs and the proteins they encode [6, 7]. While there has been significant progress in identifying the Pol II dependent transcripts (primarily mRNAs) required for early phase longterm synaptic plasticity, the gene products responsible for late-phase and maintenance remain elusive. The transcription products of RNA polymerase I (Pol I), responsible for producing non-(protein) coding ribosomal RNA, have been left unexplored despite the fact that Pol I transcription constitute more than 50% of nascent RNA synthesis in a cell (reviewed by [8, 9]). Each stage of ribosome biogenesis corresponds to a structural feature of the nucleolus, such that ultra-structural features, (e.g., the size and shape of the nucleolus), directly relate to nucleolar function and the production of ribosomes (reviewed by [12])

Methods

Results

Conclusion