Local control of protein translation during synaptic plasticity.

Long-term synaptic plasticity underlies learning and memory by tuning neural circuitry. A major process that underlies synaptic plasticity is the morphological modification of dendritic spines, which house the postsynaptic machinery. Recent studies show that numerous microRNAs (miRNAs) modulate the local translation of proteins that control spine morphology in response to stimulation. MiRNAs are small endogenous RNAs that mediate silencing of mRNA targets by associating with Argonaute (Ago) proteins in the RNA-induced silencing complex (RISC). Neuronal-specific miRNAs regulate various aspects of neuronal function and have important roles in brain disorders such as Alzheimer’s, Parkinson’s, ASD and others.

A key question is how “local” is this control of translation, i.e., does gene silencing spread along the dendrite to neighbouring unstimulated synapses, and if so, how is this regulated? This is important because dominant theories of Hebbian learning assume that plasticity is synapse-specific, even though emerging evidence suggests otherwise. Hence this research could lead to a major revision of how learning works in the brain. Recent work from the Hanley lab has defined mechanisms for rapidly increasing miRNA-mediated gene silencing in response to NMDA receptor stimulation. Our hypothesis is that these mechanisms regulate RISC activity close to the stimulated spine to modulate local miRNA-dependent translation and hence influence the morphology of a small number of neighbouring spines.

The main experimental approach will be single-spine stimulation of cultured neurons, followed by confocal imaging techniques to analyse changes in spine morphology and to define sites of nascent translation of specific proteins. The project will investigate the mechanisms that mediate local control of translation via molecular replacement approaches to introduce mutations in relevant protein machinery. In tandem with the experiments, the project will test our hypotheses by developing a set of molecular-level computer simulation models to dissect parts of the system that are not experimentally dissociable.

We are looking for an enthusiastic and innovative student with an excellent degree in neuroscience, biological or medical science. The project will be carried out under the expert supervision of Dr. Jonathan Hanley (neuronal cell biology) and Dr. Cian O’Donnell (computational biology). The cell imaging and image analysis will be carried out in the state-of-the-art Wolfson Bioimaging Facility at the University of Bristol, with the expert assistance of their technical team. For further information on this project, please contact Jonathan Hanley ([Email Address Removed]).