Deciphering the Role of lncRNA SLAMR in Synapse Function and Long-term Memory Storage

About This Grant

Project Summary Local protein synthesis at dendritic synapses undergoing morphological plasticity is essential for late long-term potentiation (L-LTP) and subsequent memory consolidation. Anterograde transport of mRNAs to these synapses supports local protein translation. However, non-coding RNAs (ncRNAs), including long non-coding RNAs (lncRNAs), are also transported to dendritic synapses alongside mRNAs. Despite their presence, the roles and mechanisms of lncRNAs in dendritic function and synaptic structural plasticity remain poorly understood. Our previous work identified SLAMR (Synaptically Localized Activity-Modulated lncRNA) as a lncRNA transported to dendritic spines following neuronal stimulation. SLAMR modulates local translation and is essential for activity- dependent changes in spine size. Loss of SLAMR function decreases translation and spine density, while its gain of function enhances both translation and spine density. Additionally, SLAMR expression increases in the hippocampal CA1 region following contextual fear conditioning, and its knockdown inhibits fear memory consolidation. However, the mechanisms by which SLAMR modulates neuronal translation and its role in synaptic signaling remain unclear. I hypothesize that SLAMR directly interacts with translation factors to modulate dendritic translation, and that this activity is crucial for its role in synaptic plasticity and memory consolidation. To test this hypothesis, Aim 1 will investigate whether SLAMR directly interacts with canonical translation machinery. Using in vitro translation and immunoprecipitation assays, I will assess SLAMR’s interactions with translation factors. Negative controls will include antisense SLAMR and the unrelated lncRNA Gas5. Additionally, targeted ribosome affinity purification will identify mRNAs whose translation is modulated by SLAMR. I will validate these targets using puromycin proximity ligation (Puro-PLA), fluorescence in situ hybridization (FISH), spine imaging, and whole-cell patch-clamp recordings. In Aim 2, I will explore the effects of functional manipulations of SLAMR on hippocampal neuron morphology and signaling ex vivo. Dendritic branching and spine morphology will be analyzed using lightsheet and stimulated emission depletion (STED) microscopy, respectively, while synaptic properties will be assessed through whole-cell and extracellular patch- clamp recordings. Behavioral tests will evaluate the impact of SLAMR gain of function on long-term memory storage. Together, these studies will provide new insights into SLAMR’s role in hippocampal synapse function and plasticity, potentially uncovering therapeutic strategies to enhance memory or dendritic branching through localized translation stimulation.