A CREB2-targeting microRNA is required for long-term memory after single-trial learning

AbstractAlthough single-trial induced long-term memories (LTM) have been of major interest in neuroscience, how LTM can form after a single episode of learning remains largely unknown. We hypothesized that the removal of molecular inhibitory constraints by microRNAs (miRNAs) plays an important role in this process. To test this hypothesis, first we constructed small non-coding RNA (sncRNA) cDNA libraries from the CNS ofLymnaea stagnalissubjected to a single conditioning trial. Then, by next generation sequencing of these libraries, we identified a specific pool of miRNAs regulated by training. Of these miRNAs, we focussed on Lym-miR-137 whose seed region shows perfect complementarity to a target sequence in the 3’ UTR of the mRNA for CREB2, a well-known memory repressor. We found that Lym-miR-137 was transiently up-regulated 1 h after single-trial conditioning, preceding a down-regulation ofLym-CREB2mRNA. Furthermore, we discovered that Lym-miR-137 is co-expressed withLym-CREB2mRNA in an identified neuron with an established role in LTM. Finally, using anin vivoloss-of-function approach we demonstrated that Lym-miR-137 is required for single-trial induced LTM.