Investigations on synaptic plasticity: new tools and perspectives

For decades, neuroscientists have sought to understand the neural basis of learning and memory. As yet no unified model has emerged, although it is widely agreed that synaptic plasticity plays a pivotal role. In consequence, a great deal of research has focused upon the characterisation of synaptic plasticity both in vitro and in vivo. While the advances have been impressive, substantial gaps remain that may be slowing the identification of the precise relationship between synaptic plasticity and learning and memory: (1) there is a paucity of research examining presynaptic plasticity mechanisms and presynaptic receptor functions; (2) synaptic dynamics are studied in behaving animals without consideration of the impact of endogenous factors, even though it looks to be clear that hormone signalling impacts upon synaptic processes: (3) An accurate assessment of synapse biology with respect to cognitive function can only arise from studies in living animals, an ambition that will require the development of new imaging tools. In this thesis I begin to address each of these points. First, using a combination of optical and electrophysiological tools I provide a functional framework for presynaptic NMDA receptor signalling that has been previously lacking. I show that the specific subunit expression at presynaptic terminals is important as it regulates Ca2+ dynamics. Second, I demonstrate that oestrogen, a neuromodulator, lowers the threshold of plasticity in several brain regions, emphasising how important it is to consider hormone status when studying synaptic dynamics. Finally, I implement several advances to a multimode fibre based minimally invasive system for high-resolution brain imaging, including the first examples of two-photon MMF imaging of biological tissue and successive imaging cycles through a multimode fibre