Molecular and functional diversity of granule cell--Purkinje cell synapses – SynBin

Synaptic plasticity is essential to all learning and memory. Plasticity modifies synaptic strength and the principal mechanism is regulation of the number of synaptic receptors. Simple learning theory suggests that synapses of a given type will be identical except for variation of receptor numbers resulting from prior plasticity, but there is evidence at several synapse types that other proteins or properties also vary. The significance of these observations has not been explored, but the variations could serve a number of functions, including more capable learning algorithms. We hypothesise that synapses of a given type can adopt distinct molecular and functional profiles between which multiple proteins vary their expression in concert. We aim to characterise these using immunohistochemistry, 3D STED super-resolution microscopy, patch-clamp recordings of unitary synaptic currents and high-speed imaging of calcium signalling. We shall focus on the cerebellar granule cell--Purkinje cell synapse, an important plastic synapse in its own right, but also one where evidence supports the existence of complex synaptic profiles potentially associated with silent synapses. When establishing the molecular and functional profiles of unitary synapses we shall verify or disprove the existence of the large majority of silent synapses that has been conjectured. Our interdisciplinary project will provide a comprehensive characterisation of intersynaptic variability, and of the existence and nature of distinct synaptic profiles. This information will provide a foundation for developing future hypotheses regarding the mechanisms of synaptic computations, plasticity and their role in learning and memory.