Orphan C/D box snoRNAs are associated with fear-related memory processes in mice.

C/D box small nucleolar RNAs (snoRNAs) comprise a class of small noncoding RNAs with important regulatory effects on cellular RNA function. Although it is well established that snoRNAs coordinate the post-transcriptional modification of pre-ribosomal and small nuclear RNAs by 2'-O-methylation, which leads to enhanced RNA stability, whether they are involved in memory-related processes remains relatively unexplored. Using targeted sequencing, we have identified more than 150C/D box snoRNAs in the prefrontal cortex of male C57BL/6 J mice, including 31 which are differentially expressed in response to fear extinction learning, and 2 putative novel C/D box snoRNAs. A subset of these snoRNAs, including many orphans, are enriched in the synaptic compartment and show dynamic changes in subcellular localization during learning. Fear extinction learning-induced increases in synapse-enriched snord64 were accompanied by increased 2'-O-methylation within the 3-UTR of the mRNA encoding the ubiquitin ligase RNF146; snord64 knockdown proportionally reduced this methylation, providing correlative evidence for snord64 as the methylation guide. These findings reveal a population of experience-dependent, synaptically localized snoRNAs and implicate C/D box snoRNA activity in the epitranscriptomic regulation of synaptic mRNAs during fear extinction learning.