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

Project description

Neurotransmitter release site plasticity: profiling synaptic gatekeepers

Neural communication relies largely on chemical neurotransmitters that are released from the presynaptic neuron, travel across the synapse and induce a signal in the postsynaptic cell. The neurotransmitters, packaged in synaptic vesicles, accumulate in the axon terminal of the presynaptic neuron like cargo waiting to be released. The number of synaptic vesicles greatly outnumbers that of release sites, tasking the sites with regulating how much chemical "information" leaves the synapse. Synaptic plasticity, changes in the synaptic machinery and processes, underlies important functions such as stable information flow, learning and memory. The ERC-funded PlasticSite project will investigate release site plasticity on timescales of milliseconds, minutes and days with a focus on conserved Unc13 release site proteins.


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.

Host institution

Net EU contribution
€ 2 000 000,00
1165 Kobenhavn

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Danmark Hovedstaden Byen København
Activity type
Higher or Secondary Education Establishments
Total cost
€ 2 000 000,00

Beneficiaries (1)