Research focus

​How does the nervous system transmit electrical pulses between neurons, and how is this process affected in neuronal disease?

We know that neurons talk to one another using small transmitter-filled synaptic vesicles that fuse with the neuronal membrane to release neurotransmitters, activating the next cell in line. While considerable progress has been made in identifying proteins present at the synapse, the role of many of them in controlling synaptic vesicle fusion, vesicle reformation at the plasma membrane and trafficking within the nerve terminal remain poorly defined. In the laboratory of neuronal communication, we address key aspects of neuronal function by employing a genetic approach using fruit flies as a model: we screen for mutations in critical genes and reveal their function by analyzing mutant phenotypes. Given the experimental advantages, flies are an ideal system to study vesicle recycling. In particular, we combine Drosophila genetics with electrophysiology, electron microscopy and live imaging of synaptic processes. The ability to apply these assays to one single type of synapse is unique and very powerful, allowing us to propose very specific functions for the proteins studied.

As a general strategy, in the lab we employ genetic screens to identify and characterize components affecting synaptic function. In one such approach we are screening the Drosophila genome by feeding flies chemical mutagens, and we use simple electrophysiological assays to isolate genes that impact the synapse. Several of the genes identified in this screen are now under investigation, and our studies continuously reveal exciting aspects of vesicle recycling and synaptic function. Interestingly, several genes that we have identified using this approach have been linked to neurological disease, including Parkinson’s disease and Amyotrophic Lateral Sclerosis, further underscoring the central involvement of neuronal communication in neuronal disease.

Building on this experience, in a second approach to identify novel genes that play a role in synaptic transmission, we are systematically testing genes implicated in neurological disease for defects in synaptic function or development. The ability to combine human disease phenotypes with genetic screening strategies using simple assays is relatively unique, and will provide new insights into common processes that underlie neurological disease progression and synaptic transmission. Already we are seeing a convergence of our two screen approaches, where our chemical mutagenesis screen identifies mutations in neurological disease genes, and conversely our neurological disease gene screen points to novel players in synaptic function, for example Rab7. Hence, we believe that our screen approaches are synergistic and will, when combined, shed new light on mechanisms of synaptic communication in healthy and diseased neurons.

Watch the Neuron video about the work on the role of ELP3 at the synapse: