Jakob Balslev Sørensen Lab

My group has expertise in studying the molecular and cellular mechanisms of neurotransmitter release in chemical synapses and in neuroendocrine cells.

Group Leader

Professor Jakob Balslev Sørensen

Department of Neuroscience
Mærsk Tower, room 07-4-56

E-mail: jakobbs@sund.ku.dk
Phone: +45 5168 0499

Research Focus

The human brain contains up to 1015 (i.e. a quadrillion) synaptic connections between its neurons. Most of these synapses are chemical, i.e. they work by releasing a chemical (a neurotransmitter) via fusion of a synaptic vesicle with the plasma membrane. The same mechanism (exocytosis) underlies the release of water-soluble hormones, such as insulin. Synaptic transmission is triggered by the arrival of an action potential within a fraction of a millisecond, and it is actively regulated over the long and short term, which allows information processing, learning and memory. Mutation, dysregulation or other insults to the synapse can lead to a number of brain diseases characterized by unbalanced or ineffective network activity, such as epilepsy, Intellectual Disability, and schizophrenia, whereas other synaptic problems lead to neurodegeneration. These diseases are sometimes referred to as ‘synaptopathies’, because they start at the synapse.

My group has expertise in studying the molecular and cellular mechanisms of neurotransmitter release in chemical synapses and in neuroendocrine cells. We do optical and electrophysiological measurements on living cells, and combine this with genetic and molecular biology methods (mouse knockouts, viral expression). We have recently started using cryo-electron microscopy, which delivers the promise to visualize single proteins in their native cellular environment. We work with the proteins, which are directly linked to exocytosis, i.e. SNARE-proteins, synaptotagmins, Munc18, Munc13 etc.

The key goals of the laboratory include:

i) identifying the components and detailed mode-of-action of the machinery for neurotransmitter release, including the mechanism by which Ca2+ triggers exocytosis. We are also interested in the molecular differences between different (synchronous, asynchronous and spontaneous) release phases, which are necessary to keep balanced network activity,

ii) understanding how the release mechanisms are regulated physiologically, for instance by G-protein coupled receptors leading to phosphorylation, or by lipids (phosphatidylinositol-4,5-bisphosphate, diacylglycerol), to ensure exocytotic and presynaptic robustness and plasticity,

iii) determine how these mechanisms are affected by disease (e.g. epilepsy, ADHD and Intellectual Disability, which are known to be correlated to mutations in the release machinery),

iv) discover the difference between synaptic insults and mutation that leads to functional problems (e.g. epilepsy) and those that lead to neurodegeneration.

v) analyze the link between synaptic dysfunction and impaired network function, which can lead to e.g. epilepsy.

Key publications

  • Houy S., Groffen A.J., Ziomkiewicz I., Verhage M., Pinheiro P.S., and Sørensen J.B. (2017). Doc2B acts as a calcium sensor for vesicle priming requiring synaptotagmin-1, Munc13-2 and SNAREs. Elife 6. pii: e27000.
  • Walter A.M.*,Müller R., Tawfik B., Wierda K.D.B., Pinheiro P.S., Nadler A., McCarthy A.W., Ziomkiewicz I.,  Kruse M., Reither G., Rettig J., Lehmann M., Haucke V., Hille B., Schultz C.* and Sørensen J.B.* (2017) Phosphatidylinositol 4,5-bisphosphate optical uncaging potentiates exocytosis. (*: corresponding authors). Elife 6: e30203.
  • Schupp M., Malsam, J., Ruiter M., Scheutzow A., Wierda K.D.B., Söllner T.H., and Sørensen J.B. (2016). Interactions between SNAP-25 and synaptotagmin-1 are involved in vesicle priming, clamping spontaneous and eliciting evoked neurotransmission. J. Neurosci. 36:11865-11880.
  • Schotten S., Meijer M., Walter A.M., Huson V., Mamer L., Kalogreades L., ter Veer M., Ruiter M., Brose N., Rosenmund C., Sørensen J.B.*, Verhage M.*, and Cornelisse L.N.* (2015). Additive effects on the energy barrier for synaptic vesicle fusion cause supralinear effects on the vesicle fusion rate. *Equal contributions. Elife4:e05531.
  • Walter A.M., Kurps J., de Wit H., Schöning S., Toft-Bertelsen T.L., Lauks J., Ziomkiewicz I., Ngatchou Weiss A., Schulz A., Fischer von Mollard G., Verhage M., and Sørensen J.B. (2014). The SNARE protein vti1a functions in
    dense-core vesicle biogenesis. EMBO J 33,1681-1697.
  • Pinheiro P.S., De Wit H., Walter A.M., Groffen A.J., Verhage M., and Sørensen J.B. (2013). Doc2b synchronizes secretion from chromaffin cells by stimulating fast and inhibiting sustained release. J. Neurosci. 33, 16459-16470.
  • Mohrmann R., De Wit H., Connell E., Pinheiro P.S., Leese C., Bruns D., Davletov B., Verhage M., and Sørensen J.B. (2013). Synaptotagmin interaction with SNAP-25 governs vesicle docking, priming, and fusion triggering. J. Neurosci. 33, 14417-14430.
  • Mohrmann R., De Wit H., Verhage M., Neher E., and Sørensen J.B. (2010). Fast vesicle fusion in living cells requires at least three SNARE-complexes. Science 330, 502-505.
  • Walter A.M., Wiederhold K., Bruns D., Fasshauer D., and Sørensen J.B. (2010). Synaptobrevin N-terminally bound to SNAP-25:syntaxin defines the primed vesicle state in regulated exocytosis. J. Cell Biol. 188, 401-413.
  • Sørensen J.B. (2009). Conflicting views on the membrane fusion machinery and the fusion pore. Annu. Rev. Cell Dev. Biol. 25, 513-537.