The CPEB3 ribozyme modulates hippocampal-dependent memory

Abstract

A self-cleaving ribozyme mapping to an intron of the cytoplasmic polyadenylation element binding protein 3 (CPEB3) gene has been suggested to play a role in human episodic memory, but the underlying mechanisms mediating this effect are not known. The ribozymes self-scission half-life matches the time it takes an RNA polymerase to reach the immediate downstream exon, suggesting that the ribozyme-dependent intron cleavage is tuned to co-transcriptional splicing of the CPEB3 mRNA. Here we report that the murine ribozyme modulates its own host mRNA maturation in both cultured cortical neurons and the hippocampus. Inhibition of the ribozyme using an antisense oligonucleotide leads to increased CPEB3 protein expression, which enhances polyadenylation and translation of localized plasticity-related target mRNAs, and subsequently strengthens hippocampal-dependent long-term memory. These findings reveal a previously unknown role for self-cleaving ribozyme activity in regulating experience-induced co-transcriptional and local translational processes required for learning and memory.