Pre- and postsynaptic determinants of neurotransmitter release at individual release sites. (360G-Wellcome-108201_Z_15_Z)

Connections between neurons are made up of several individual release sites, each with a different probability of releasing neurotransmitter upon arrival of an action potential. How pre- and postsynaptic neuron work in concert to regulate release probability (Pr) at different connection points is still unclear. A novel combination of techniques will be used to study Pr at individual active zones and to identify the mechanisms involved in its regulation. We will test the hypothesis that Pr is reg ulated in concert by both pre- and postsynaptic compartments using electrophysiology, live fluorescence imaging and serial electron microscopy both at cortical boutons and at the Calyx of Held, a giant synapse in the auditory pathway. By labelling pre- or postsynaptic cortical neurons, we will ascertain whether the presynaptic origin as well as the target neuron play a key role in setting Pr at the cellular and network-level. To reduce confounding elements, such as compartmentalised postsynaptic activity, we will use the Calyx of Held, where hundreds of active zones contact the same postsynaptic soma. This project will identify the mechanisms by which individual terminals embedded in a network set synaptic strength; with impact on detection of synaptic changes and degeneration at an early stage.