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Neurons in the brain transmit information to each other through specialized connections called synapses. This process is initiated when the action potential invades the presynaptic terminal, which in turn causes the fusion of transmitter-filled vesicles with the presynaptic membrane releasing its content. Then transmitters can diffuse through the synaptic cleft and activate postsynaptic receptors thereby altering the postsynaptic membrane potential. This process is highly complex yet occurs with amazing speed and astonishing precision millions of times at every second within our brain. Moreover, functional properties of synapses within the brain can vary dramatically and can undergo rapid and lasting changes, and this in turn affect how information in the brain are encoded, and even how we learn and forget, how we think and feel, how we sense our environment and act.
In our lab we study the basic principles of synaptic transmission with a major focus on the process of neurotransmitter release. In particular, we examine the molecular mechanisms underlying this process in central synapses. Within the presynaptic terminal, release of neurotransmitter-filled vesicles is restricted to active zones. In a series of functional highly coordinated and regulated steps synaptic vesicles are filled with neurotransmitter, tether to specific release sites at the active zone, prime to reach fusion competence, and finally fuse in a calcium-triggered event with the plasma membrane to release the neurotransmitter into the synaptic cleft. This chemical signal is than recognized and transduced into an electrical signal by activation of specific receptors at the postsynaptic site.
Elucidation of the mechanisms of synaptic transmission and its regulation is central to the understanding of brain function and dysfunction. Our goal is to quantify and kinetically resolve individual steps within this vesicle cycle. We want to understand which presynaptic proteins; protein-domains and individual residues mediate these steps. Furthermore, we want to identify molecules and mechanisms contributing to heterogeneity in synaptic function. Finally, we want to know how changes of synaptic function such as release probability or short-term plasticity affects the behavior of neurons within defined neuronal networks.
To understand the complexity of synaptic transmission and neurotransmitter release an integrative approach including biochemistry, genetics, structural and functional analysis is required. We functionally characterize synaptic properties of genetic modified mice that bear deletions of- or carry mutations within presynaptic proteins. By using cultured primary neurons and slices we are able to apply the following methods: We use electrical and optical recording techniques, such as standard patch-clamp electrophysiology and Calcium-imaging, to study synapses in their function and plasticity. We further use light and electron microscopy to study the structure of synapses and how these structures change during plastic events and under pathophysiological conditions.
These techniques are also powerful tools in studying the mechanisms that underly diseases such as epilepsy, autism, schizophrenia and many other neurological disorders. Dramatic advances in the field of human and molecular genetics have shown that these diseases are in part synaptopathic, as these diseases are often associated with mutation in synaptic proteins.