Gas5 regulates early-life stress-induced anxiety and spatial memory

Early-life stress (ES) induced by maternal separation (MS) remains a proven causality of anxiety and memory deficits at later stages of life. Emerging studies have shown that MS-induced gene expression in the hippocampus is operated at the level of transcription. However, the extent of involvement of non-coding RNAs in MS-induced behavioural deficits remains unexplored. Here, we have investigated the role of synapse-enriched long non-coding RNAs (lncRNAs) in anxiety and memory upon MS. We observed that MS led to an enhancement of expression of the lncRNA growth arrest specific 5 (Gas5) in the hippocampus; accompanied by increased levels of anxiety and deficits in spatial memory. Gas5 knockdown in early life was able to reduce anxiety and partially rescue the spatial memory deficits of maternally separated adult mice. However, the reversal of MS-induced anxiety and memory deficits is not attributed to Gas5 activity during neuronal development as Gas5 RNAi did not influence spine development. Gene Ontology analysis revealed that Gas5 exerts its function by regulating RNA metabolism and translation. Our study highlights the importance of MS-regulated lncRNA in anxiety and spatial memory.image The non-coding RNA-based mechanisms of early-life stress-induced gene expression in the hippocampus and its implications in anxiety and memory are poorly resolved. The study fills this void by identifying a synapse-enriched lncRNA, growth arrest specific 5 (Gas5), that is induced by maternal separation, a paradigm for early-life stress. Maternal separation elevates anxiety and memory deficits that are partially rescued by altering the level of Gas5 following early-life stress. We provide an RNA-dependent new layer of post-transcriptional control involving translation and RNA processing to mitigate insult from early-life stress.image