Long non-coding RNAs at the synapse: Implications in synaptic plasticity and memory

Abstract

Long non-coding RNAs (lncRNA) is emerging as a key regulatory RNA in the brain. The activity of lncRNAs in neurons have been majorly limited to the nucleus and our understanding of their functions in subcellular space remains elusive. We have used the genome-wide transcriptomic profiling of total RNA isolated from the synaptic compartment and identified synapse-enriched lncRNAs from the mouse hippocampus. Among these transcripts, we find a synapse-centric role for a novel lncRNA, SynLAMP (Synapse-enriched LncRNA Associated with Memory and Plasticity). SynLAMP is specifically transported to the synaptic compartment upon contextual fear conditioning (CFC). We observed that CFC triggers interaction between SynLAMP and translation repressor FUS. The knockdown of SynLAMP prevents activity-induced dendritic translation. Our data suggests that SynLAMP functions as an activity-regulated molecular decoy to sequester translation repressor FUS. We find that the knockdown of SynLAMP partially occludes the fear memory. The decoy function of synaptic lncRNAs was further favoured by our findings on Cerox1 (Cytoplasmic endogenous regulator of oxidative phosphorylation 1), a synapse-enriched lncRNA that acts as a competitive decoy for miRNAs. We observed that Cerox1 levels decrease following sleep loss, a condition known to impair memory. Sleep deprivation or Cerox1 knockdown led to reduced mitochondrial Electron Transport Chain (ETC) activity and diminished ATP production, whereas overexpression of Cerox1 was sufficient to restore ETC function and ATP levels, even under conditions of sleep deprivation. This regulation is mediated by Cerox1’s ability to sequester miRNAs that target both Cerox1 and essential subunits of ETC complex I, thereby sustaining their expression in a sleep-dependent manner. Importantly, overexpression of Cerox1 alleviated memory deficits caused by sleep loss, while a Cerox1 variant lacking miRNA-binding sites failed to produce such effects. Collectively, these findings uncover a previously unrecognized mechanism of memory regulation mediated by the decoy activity of synapse-enriched lncRNAs.