The Role of miRNA in Activity-Dependent Synaptic Plasticity

Abstract

During processes like learning and memory, neural activity dynamically remodels synaptic connectivity which is critical for adaptive behavior and memory storage. At the molecular level, regulatory control of transcription and translation are indispensable for this process. Accordingly, the neuron is equipped with a robust arsenal of regulatory sensors that tightly couple changes in neural activity with transcription and protein synthesis. Within this regulatory framework, individual mRNA translation can be terminally repressed or temporarily stalled by the action of microRNAs (miRNAs). miRNAs are deployed downstream of neural activity to mediate rapid modulation of protein synthesis locally within synaptic compartments. Such regulation is distinct from classic modes of transcriptional control that regulate gene expression on relatively broad spatial and temporal scales. In contrast, the regulatory action of miRNAs can be acutely triggered to regulate mRNA translation for rapid activity-dependent modulation of local synaptic structure. Here, we have used the Drosophila neuromuscular junction to broadly survey the regulatory contributions of human conserved miRNAs during structural plasticity of the synaptic terminal. Importantly, I have discovered miRNA-973 (miR-973) as a novel regulator of synaptic structure downstream of neural activity. Accordingly, loss of miR-973 function leads to an activity-dependent degeneration of synaptic boutons. In this context, bouton decay is marked by the unique accumulation of peri-synaptic membranous debris, which is consistent with degenerative phenotypes. Mechanistically, I have shown miR-973 regulates Down Syndrome Cell Adhesion Molecule 2 (DSCAM2), a known regulator of synaptic endocytosis and vesicular dynamics. Importantly, the synaptic degeneration phenotypes associated with miR-973 loss of function can be rescued by DSCAM2 inhibition, which underscores an important role for the miR-973-DSCAM2 regulatory interaction during plasticity of synaptic structure in an activity-dependent context.