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Molecular mechanisms of presynaptic plasticity

Project description

At the site of information transmission, the transmitter finally gets the attention it deserves

Donald Hebb first postulated the presence of activity-dependent changes in neurons in his seminal book published in 1949. Since then, scientists have advanced our understanding of neuronal interactions tremendously, evaluating synaptic plasticity with ever-increasing temporal and spatial resolution and, in some cases, even correlating electrophysiological and molecular changes with organism behaviour. However, despite the intense interest in and significance of what happens at the synapse relative to cognition and behaviour, the presynaptic changes have largely taken a backseat to the postsynaptic changes. The EU-funded project PreSynPlast is using a variety of in vitro preparations and electrophysiological and molecular studies to provide an unprecedented window onto presynaptic plasticity. Outcomes will have implications for our understanding of the brain, for computational models and computing, and for novel angles on common diseases.

Objective

The ambitious goal of this project is to reveal the molecular mechanisms of presynaptic plasticity in the vertebrate brain. Synaptic plasticity occurs in the form of alterations in both presynaptic neurotransmitter release and postsynaptic receptor function. However, due to technical reasons and in contrast to intensely studied postsynaptic plasticity, the presynaptic half of the brain’s synaptic plasticity remains enigmatic. This is a crucial knowledge gap for our understanding of learning and memory.
My ambitious aim is therefore to uncover the molecular and biophysical mechanisms of presynaptic plasticity. Building on my strong track record in presynaptic research, my group made a technical breakthrough by establishing patch-clamp recordings from small nerve terminals of cultured neocortical neurons with unprecedented high resolution. In addition, we use an innovative super-resolution-microscopy approach resolving the rearrangement of proteins within the presynaptic neurotransmitter release site, which allows high-throughput screening of all major classes of synaptic genes for their involvement in presynaptic plasticity. To reveal the neuron- and plasticity-type specificity, the identified molecular pathways will be analysed in different types of neurons in culture and acute brain slices. Building on these unique abilities, I will also investigate physiological and pathophysiological modulations of presynaptic plasticity. Specifically, I will test the hypothesis that metabolic constraints regulate presynaptic plasticity and that the amyloid pathology of Alzheimer’s disease impacts presynaptic plasticity.
Thus, for the first time in the history of neuroscience, neocortical nerve terminals can be investigated with direct electrophysiological recordings and super-resolution microscopy providing unprecedented spatial and temporal resolution for the analysis of presynaptic plasticity. The results could pave the way for new approaches treating neurological diseases.

Host institution

UNIVERSITAET LEIPZIG
Net EU contribution
€ 1 609 937,00
Address
RITTERSTRASSE 26
04109 Leipzig
Germany

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Region
Sachsen Leipzig Leipzig
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 1 609 937,00

Beneficiaries (1)