Principles of neurotransmitter signal formation in the brain. (360G-Wellcome-084311_Z_07_A)

Memories are formed trough use-dependent modification of synaptic circuits of the brain. Establishing the cellular basis of such modification, in health and disease, remains a fundamental challenge in neurobiology. Our aim is to elucidate mechanisms through which presynaptic mechanisms and the synaptic environment control formation of fast neurotransmitter signals at central synapses. We are proposing a multi-disciplinary investigation focused on individual excitatory synapses and their microenv ironment in the hippocampal circuitry. Our main research objectives include: - to determine mechanisms through which electrotonic signal propagation and target cell-specific actions of presynaptic kainate receptors affect transmission in the mossy fibre circuitry; - to establish the involvement of glia in use-dependent modifications of glutamatergic signalling; - to determine how the extracellular environment affects diffusion of fast neurotransmitters; - to elucidate presyna ptic mechanisms underlying fluctuations in the release probability and to evaluate the amount of glutamate released by a single synaptic vesicle. The study will capitalise on the existing experimental basis combining single-cell electrophysiology with state-of-the-art multi-photon microscopy techniques and extensive biophysical modelling. The project will also benefit from the first-class research environment and from collaboration with several groups leading in their areas of expertise.