Molecular and Theoretical Neuroscience (Alexander Walter)

Our lab is interested in the following research questions:

  • Which proteins optimize synapses for fast release?
  • How are exo- and endocytosis coupled?
  • What is the basis of synaptic heterogeneity?

The presynaptic machinery for exo- and endocytosis

Fast chemical transmission across synaptic contacts requires the timed release of neurotransmitters from the presynaptic neuron. At the presynapse, the neurotransmitter is stored in small synaptic vesicles. To release the transmitter, synaptic vesicles undergo exocytosis: they fuse with the cell membrane to discharge the neurotransmitter which then activates specialized receptors on the postsynaptic side.

 

Different types of exocytosis have been described: while vesicles can release spontaneously without any stimulation, typical signal transduction relies on evoked exocytosis activated by action potentials which depolarize the presynaptic membrane. This leads to the activation of specialized ion channels which mediate calcium influx and thereby trigger vesicle fusion by activating a calcium sensing protein on the vesicle. At least two discernible types of evoked release can be distinguished based on their kinetics. The fastest form of exocytosis is synchronous release, induced extremely rapidly, with less than a millisecond between the arrival of the action potential and the activation of the postsynaptic response. In most if not all neurons, synchronous release is accompanied by asynchronous release, which is evoked by action potentials with looser temporal coupling. Why these different modes of exocytosis coexist and what the underlying molecular determinants for their segregation are is not well understood.


Endocytosis, the internalization of membrane from the cell surface counterbalances exocytosis by the re-uptake of the surplus membrane deposited after exocytosis. It occurs rapidly after evoked exocytosis to ensure constant amounts of plasma membrane and is essential for continued neuronal activity because it is the first step of the vesicle re-cycling reaction.

Using electrophysiological and live-cell imaging approaches we investigate exo- and endocytosis. We are particularly interested in a class of large proteins that form stable scaffold-like structures at the presynapse. Our model system is the neuromuscular junction (NMJ) of developing Drosophila Melanogaster larvae, which is well suited for our investigations due to its experimental accessibility for physiological measurements like voltage clamp recordings and live cell imaging (the organism is light transparent). Furthermore, since Drosophila is well established as a genetic model system, it is especially suited to investigate protein functions by mutagenesis studies. We also combine the results of the molecular perturbation studies with kinetic mathematical modeling in order to relate the action of individual proteins to individual steps of the exo-endocytosis reaction cascade.

Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP)
Campus Berlin-Buch
Robert-Roessle-Str. 10
13125 Berlin, Germany
+4930 94793 - 100 
+4930 94793 - 109 (Fax)
info(at)fmp-berlin.de

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