EASTBIO: Studying brain architecture using molecular imaging of single synapses

A major conceptual advance in our understanding of the mammalian nervous system is that the vast numbers of synapses – the junctions between nerve cells - are highly diverse [1]. Each synapse type is characterised by its protein composition and different combinations of proteins are the signatures of synapse type. Imaging of the molecular composition of individual synapses shows synapse types are not spatially distributed in a random fashion but instead are organised into a “synaptome architecture” [1]. Synapse diversity and synaptome architecture confers important biological properties on the brain including the capacity to store and retrieve information and thereby program innate behaviours and learning and memory.

There is a pressing need to develop new approaches to study the protein composition of single synapses in brain tissue and use these approaches to understand the mechanisms of synapse diversity and synaptome architecture. This project will involve the development and integration of confocal and super-resolution light microscopy, molecular labelling, biochemistry and mouse genetic techniques to explore this problem. Labelling of multiple synapse proteins using genetically modified mice expressing synaptic proteins fused to multifunctional tags including Halo, CLIP and SNAP tags or antibodies (labelled for use in DNA PAINT2) will be used to visualize proteins with confocal and super-resolution microscopy, enabling sub-synaptic resolution of protein localisation3. Classification of synapse types will employ machine learning techniques1.

The project will generate large datasets spanning the scales of the nervous system from single synapses to the brain-wide scale. We will use these cross-cutting laboratory and data analysis techniques to ask how much synapse diversity there is and how it is sequentially built during early postnatal development in the mouse. The student will be trained to tackle fundamental scientific questions in a vibrant atmosphere in two laboratories with complementary and wide-ranging expertise using cutting edge methods in neuroscience and biophysics.