MULTISCALE REGULATION OF SYNAPTIC PLASTICITY BY CODING AND NONCODING RNAS DURING DEVELOPMENT

Experience-dependent refinement of neuronal circuits during postnatal development relies on tightly regulated windows of heightened structural plasticity. While transcriptional programs shaping critical period plasticity are well characterised, far less is known about how local RNA-based mechanisms contribute to synaptic remodelling. In particular, the role of synapse-associated mRNAs and microRNAs (miRNAs) in coordinating structural changes during development remains largely unexplored. Here, we examine how local RNA regulatory networks shape structural synaptic plasticity in the developing mouse visual cortex across the critical period. We find that synaptic refinement is marked by coordinated structural changes, including a progressive reduction in presynaptic bouton density accompanied by bouton enlargement, consistent with selective synaptic pruning and stabilisation. These morphological transitions coincide with transient activation of complement signalling and increased microglia-synapse interactions during peak plasticity. At the molecular level, synaptic compartments exhibit pronounced developmental reprogramming of RNA-related processes, including pathways linked to local translation, RNA processing, and vesicle trafficking. Distinct regulatory states emerge that correspond to phases of synaptic stability, heightened plasticity, and maturation. In parallel, synapse-associated miRNAs display dynamic, stage-specific expression patterns across development. Integration of miRNA and mRNA data reveals extensive post-transcriptional regulation of synaptic transcripts, converging on key genes involved in cytoskeletal organisation, protein trafficking, and synaptic proteostasis, with minimal changes in overall transcript abundance. Together, these findings highlight local RNA-mediated regulation as a central mechanism linking synaptic structure, glial signalling, and circuit maturation during developmental plasticity.