Plasticity of neurotransmitter release sites in temporal coding, homeostasis, learning and disease

ongoing

Virtually all neural computation relies on synaptic plasticity, the dynamic change of chemical synaptic communication achieved by transmitter exocytosis from vesicles at presynaptic release sites to activate postsynaptic receptors. Plasticity mechanisms must be powerful, scalable and sustainable over all timescales of neural processing. Which part of the synaptic machinery is the best suited plasticity target? The number of synaptic vesicles greatly outnumbers that of release sites, essentially making the sites gatekeepers of all neural communication. Release site plasticity could thus be pivotal to all neural processing. We recently discovered the molecular identity of release sites (conserved Unc13 proteins) and found evidence of potent release site plasticity on timescales of milliseconds, minutes and days. We are now in the position to use this molecular handle to unravel the principles of this plasticity which will be key to understand neural function, behaviour and disease. Owing to the conserved process and machinery, we will harness the power of Drosophila genetics to elucidate general mechanisms and broad relevance of three distinct release-site plasticity phenomena: 1. Release site switching for millisecond facilitation of transmission and its contribution to network pattern generation as needed for locomotion. 2. Release site activation for minutes’ potentiation of transmitter release and its role in homeostasis and learning. 3. Release site accumulation for long-lasting potentiation with regained dynamic range and its role in homeostasis and memory. Finally, disease mutations accumulate in proteins relating to release site function. We will thus (4.) investigate whether these mutations affect release site plasticity in flies and attempt treatment of their induced defects by artificial enhancement of plasticity. My work will set the stage to establish the investigation of the role of this novel and fundamental plasticity in neural function and disease.