Synaptically-targeted long non-coding RNA SLAMR promotes structural plasticity by increasing translation and CaMKII activity

Abstract

Long noncoding RNAs (lncRNAs) play crucial roles in maintaining cell homeostasis and function. However, it remains largely unknown whether and how neuronal activity impacts the transcriptional regulation of lncRNAs, or if this leads to synapse-related changes and contributes to the formation of long-term memories. Here, we report the identification of a lncRNA, SLAMR, which becomes enriched in CA1-hippocampal neurons upon contextual fear conditioning but not in CA3 neurons. SLAMR is transported along dendrites via the molecular motor KIF5C and is recruited to the synapse upon stimulation. Loss of function of SLAMR reduces dendritic complexity and impairs activity-dependent changes in spine structural plasticity and translation. Gain of function of SLAMR, in contrast, enhances dendritic complexity, spine density, and translation. Analyses of the SLAMR interactome reveal its association with CaMKIIα protein through a 220-nucleotide element also involved in SLAMR transport. A CaMKII reporter reveals a basal reduction in CaMKII activity with SLAMR loss-of-function. Furthermore, the selective loss of SLAMR function in CA1 disrupts the consolidation of fear memory in male mice, without affecting their acquisition, recall, or extinction, or spatial memory. Together, these results provide new molecular and functional insight into activity-dependent changes at the synapse and consolidation of contextual fear.

lncRNA ADEPTR loss-of-function elicits sex-specific behavioral and spine deficits

“…Among these, long noncoding RNAs (lncRNAs) have emerged as key players in modulating neuronal maturation, function, memory, and brain pathologies (Andersen et al, 2019;Grinman et al, 2019a;Li et al, 2017;Kim et al, 2023;Chanda et al, 2022;Wei et al, 2022;Ben-Tov Perry et al, 2022;Madugalle et al, 2023;Zou et al, 2023;Chanda et al, 2021;Zhang et al, 2012). Of particular significance are cytoplasmically enriched lncRNAs, which regulate RNA turnover and protein synthesis either directly or by modulating miRNA activity targeting mRNAs (Douka et al, 2021;Kleaveland et al, 2018, Grinman et al, 2019bNoh et al, 2018;Grinman et al, 2021;Liau et al, 2023, Soutschek andSchratt, 2023;Espadas et al, 2024). Despite significant advancements, genetic evidence validating the in vivo functions of many long non-coding RNAs (lncRNAs) remains limited.…”

“…Although genetically modified animals have been successfully developed to study nuclear-enriched lncRNAs and their mechanisms (Zhang et al, 2012; Sauvageau et al, 2013; Ben-Tov Perry et al, 2023), there is a lack of models for investigating cytoplasmically enriched lncRNAs. Recent research highlights the importance of these cytoplasmic lncRNAs in modulating neuronal morphology and memory (Grinman et al, 2021; Cui et al, 2022; Liau et al, 2023; Espadas et al, 2024). Additionally, the potential for sex-specific functions among lncRNAs is an area that remains largely unexplored.…”