Walter Lab

The Walter Lab aims to identify principles of synaptic transmission as well as mechanisms by which synapses adapt their input/output relationship to stabilize signal transmission or process information.


 

The Walter lab was started in April 2015 by Alexander Walter thanks to an Emmy Noether Grant by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) that funded research conducted at the Leibniz-Institut für Molekulare Pharmakologie (FMP) in Berlin. In 2020 Alexander was awarded a Young Investigator Award by the Novo Nordisk Foundation to fund his research at the Department of Neuroscience at the University of Copenhagen where the lab recently moved. Besides the PI, the group currently consists of four PhD students, one technical assistant, and visiting students.

Projects and methods of the Walter lab focus on elucidating the molecular mechanisms of chemical synaptic transmission, which allows nerve cells to communicate with one another at specialized contact sites, the synapses. There, neurotransmitters are released presynaptically and detected postsynaptically. One demand for this is that transmission must be very fast (less than 1 millisecond) to ensure meaningful communication in the nervous system. A second demand is that synapses must be able to undergo plastic changes to e.g. ensure stable communication in cases the responsiveness of cells drops or to change transmission strength to store information in neural networks. For this synaptic transmission engages a complex molecular machinery of many specialized proteins, but how these components cooperate to fulfill the demands for remarkably fast, faithful and adaptable information transfer is still unknown. Using experimental and theoretical approaches the group aims to identify these principles.

 

 

Personal Information

Name: Dr. rer. nat. Alexander Matthias Walter, MSc
Date of birth: 08.01.1981
citizenship:  German, British
email:  awalter@fmp-berlin.de; awalter@sund.ku.dk
Website: https://www.walter-lab.com/
Orchid ID: 0000-0001-5646-4750
Google Scholar: https://scholar.google.de/citations?user=4rT8Y30AAAAJ&hl=de#

Positions Held

2020-now Associate Professor for Molecular and Theoretical Neuroscience, Department of Neuroscience, Faculty of Health and Medical Sciences, Copenhagen University, Denmark
2015-now Emmy Noether Research Group Leader (part time since Aug. 2021), of the Group “Molecular and Theoretical Neuroscience” at the Leibniz-Forschungsinstitut für Molekulare Pharmakologie, Berlin, Germany
2013-2015 Postdoc, with Volker Haucke, Neurocure Cluster of Excellence, Charité Berlin, Germany
2011-2013 Postdoc with Jakob Sørensen, Department of Neuroscience and Pharmacology, University of Copenhagen, Denmark
2010-2011 Postdoc with Matthijs Verhage, Center of Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, the Netherlands

Education

2006-2010 PhD with Jakob Sørensen, Erwin Neher, Reinhard Jahn, Department of Membrane Biophysics, Max-Planck Institute for Biophysical Chemistry, Göttingen, Germany, grade dissertation: summa cum laude
2006 Master, International Max-Planck Research School (IMPRS) and Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden – Note: A (excellent), top of the class
2003 Vordiplom, Chemistry, Georg August Universität Göttingen, Germany – grade: Sehr gut
2000 Abitur (German A-levels), Gymnasium Walsrode, Germany – grade: 1.3, top of the class

3rd Party Funding

2019 Novo Nordisk Young Investigator Award (25 000 000 DKK, ~3 350 000 EUR), Award to conduct a research project at Copenhagen University, Denmark
2016-now SFB/TRR 186 Research Grant (471 120 EUR), project leader in the “Transregio“ TRR186 “Molecular Switches in the Spatio-Temporal Control of Cellular Signal Transmission“ between Heidelberg and Berlin funded by the “Deutsche Forschungsgemeinschaft” (DFG), Bonn, Germany
2015-now Emmy Noether Research Grant (2 051 700 EUR), Funding of research group, DFG Bonn, Germany
2010-2011 EMBO Long-term Fellowship (~35 000 EUR), Funding of a postdoc position

Honours and Funding

2017 Japan Neuroscience Society, Award for excellent presentation, 40th annual meeting, Tokyo, Japan
2016-now Einstein Center for Neuroscience Berlin (~35 000 EUR), funding of a PhD position
2009 59th Meeting of Nobel Laureates, Invitation to the annual meeting of Nobel Laureates 2009
2008 Excellence in Teaching Neuroscience Award, Award for the best teaching (tutorial) in the IMPRS Neuroscience curriculum, Max-Planck Research School, Göttingen
2007 Symposium Award, Award by the Society of General Physiologists, Woods Hole, MA, USA
2005-2006 Fellowship “Deutscher Akademischen Austauschdienst“ (DAAD) for a Master’s Thesis in Sweden (Karolinska Institute Stockholm), Bonn, Germany
2004-2005 Fellowship Max-Planck Society, Max-Planck Research School Neuroscience, Göttingen, Germany

Teaching Experience

2018 FENS Cajal course: Advanced imaging methods for Cellular Neuroscience, Instructor, Bordeaux, France
since 2018 Seminars in Neurophysiology, Curriculum for medical students, Charité Berlin, Germany
since 2017 Lecture: Neurophysiology for Dentistry Students, Charité Berlin, Germany
2014 Lecture and practical course in the Master’s Modul “Molecular Neurogenomics”, Freie Universität Berlin, Germany
2010 Coordination of course “Advanced Neurogenomics“, Vrije Universiteit Amsterdam, Netherlands
2006-2007 Tutor to Erwin Neher’s Lecture „Electrophysiological Techniques“, Max-Planck Research School, Göttingen, Germany

Didactic qualilfications

ongoing Qualification as German University Professor “Habilitation” with Prof. Dr. Jörg Geiger, director of the Institute for Neurophysiology, Charité University Hospital, Berlin, Germany
2020 Didactically certified implementation of a teaching project: Conception of a lecture series in physiology, assessed by the “Dieter Scheffner Fachzentrum” for University didactics, Charité University Hospital, Berlin, Germany
2020 Certified didactic training (40 hours), “Dieter Scheffner Fachzentrum” for University didactics, Charité University Hospital, Berlin, Germany
2017 Certified didactic training (21 hours), Centre for Science & Research Management, Speyer, Germany
2008 Excellence in Teaching Neuroscience Award, Award for the best teaching (tutorial) in the IMPRS Neuroscience curriculum, Max-Planck Research School, Göttingen

Invitation as Speaker to international conferences

2020 Baeza meeting of the SynGo Consortium, Baeza, Spain, Invitation to the workshop: “Synaptic Dimension of Brain Disorders Workshop” –postponed to 2021 due to Covid-19
2019 Biophysical Society Thematic Meeting, Padova, Italy, Symposium talk: “Release site recruitment and activation as mechanisms of presynaptic plasticity”
2019 Dutch Neuroscience Meeting, Lunteren, the Netherlands, Key note lecture: “Release site addition as a mode of presynaptic plasticity”
2018 Federation of European Neuroscience Societies (FENS)-forum, Berlin, course “Introduction to synaptic transmission at the central synapse”, Talk: “Synapse structure/function and diversity”
2018 EMBO Workshop “Exocytosis and Endocytosis”, Tenerife, Spain, Symposium talk: “Unc13A generates and positions synaptic vesicle release sites”
2017 International Symposia of Chromaffin Cell Biology, Sheffield, United Kingdom, Symposium talk: “Phosphatidylinositol 4,5-bisphosphate optical uncaging potentiates exocytosis in chromaffin cells”
2017 40th Annual Meeting, Japanese Neuroscience Society, Tokyo, Japan, Symposium talk: “Tight distribution of synaptic vesicle release sites generated by Unc13 synchronizes neurotransmission”
2014 INCF Neuroinformatics Congress, Leiden, the Netherlands, Symposium talk: “A catalytic slot model for exocytosis with a single release sensor effectively explains properties of neurosecretion”
2011 Exocytosis and Endocytosis Meeting, Edinburgh, United Kingdom, Talk: „A sequential secretion model with a single Ca2+-sensor explains heterogeneity in release kinetics”

Organisation of Scientific Meetings

2016 Federation of European Neuroscience Societies (FENS)-forum, Copenhagen, Denmark, Chair of Symposium S26 “Modelling of the synapse- the presynaptic side”.

Current Collaborators

Dion Dickman, Department of Biology, University of Southern California, Los Angeles, USA. Physiology of synaptic transmission
Susanne Ditlevsen, Department of Mathematical Sciences, University of Copenhagen, Denmark. Mathematical modelling of synaptic transmission
Stephan Hell, Department for NanoBioPhotonics, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany. Super-resolution microscopy
André Nadler, Max Planck Institute for Molecular Cell Biology and Genetics, Dresden, Germany. Investigation of signalling lipids using “lipid uncaging”
David Owald, Institute for Neurophysiology, Charité Berlin, Germany. Behavioural Analyses (learning and memory) of Drosophilae
Köksal Özgül, Haccettepe University, Ankara, Turkey. Investigation of synapse function in Drosophila models of human neurometabolic diseases.
Christian Rosenmund, Institut für Neurophysiologie, Charité Berlin. Molecular mechanisms of exocytosis.
David Schwefel, Institut for Medical Physics and Biophysics, Charité Berlin. Structural Biology
Stephan Sigrist, Institute for Genetics, Freie Universität Berlin, Germany. Drosophila Neurogenomics and synaptic ultra-structure
Matthijs Verhage, Vrije Universiteit Amsterdam, The Netherlands. Neural disease gene ontology.

 

Fly genetics

The fruit fly Drosophila melanogaster is very amenable to genetic modification. From the adult fly laying eggs to the 3rd instar larva we’re preferentially working with, it only takes 7-9 days. Using genetic toolboxes developed by other scientists, we can tag our protein of interest with fluorescent markers, or remove a protein the role of which we want to study.

Since its initial use by William Castles and Thomas Hunt Morgan more than 100 years ago, Drosophila melanogaster has become one of the most heavily used model organisms to study a diverse range of biological processes including genetics, embryonic development, learning, aging, and neurobiological processes. Its initial use by Morgan redefined the theory of heredity by discovering genes and found that they are located within chromosomes. This led to the first of six Nobel prizes awarded for Drosophila research (the others were awarded for the discovery that mutations are caused by X-ray, for founding the field of evolutionary developmental biology, and for the discovery of olfactory receptors, the innate immunity and finally of the circadian rhythm).

Interestingly, one convention unique to Drosophila was introduced by Morgan: the naming of genes in accordance to the phenotype their knock-down causes: the first mutation ever isolated is known as white, causing white instead of the wild type red eyes. Over the years, this convention has also led to somewhat entertaining names as “cheap-date”, naming flies that suffer from a reduced alcohol tolerance; or the opposite situation “happy hour”, naming flies that show an increased tolerance (Corl et al., 2009; Moore et al., 1998). For the research questions our lab is focused on, Drosophila is unique in its advantages. These include a relatively short generation time of about 10 days (see life cycle), an every growing genetic tool box allowing tissue- and even cell-specific expression or knock-down of genes of interest but especially a tremendous applicability to scientific methodologies (see methods section). Furthermore, 75% of all known human disease related genes have a recognizable counterpart in the Drosophila genome (Jennings, 2011) making it a perfectly suited tool to not just understand the molecular underpinnings of humans diseases, but also to study the function of these molecules in the healthy organism.

Live imaging

Biological processes are best viewed in real time and with as much temporal and spatial information as possible. Therefore, we use fluorescent probes to visualize synaptic activity and protein trafficking in live dissected larvae.

The fluorescent calcium indicator GCaMP has proven especially useful in this, and we use it to watch as the synapse releases its vesicles. Using this method, we measure the influence of synaptic proteins on signal transmission which helps us understand how the synapse works.

Super-resolution microscopy: STED

A large extent of the current understanding of biological processes comes from experiments that visualized them using various microscopic techniques including fluorescence microscopy. However, due to the Abbe diffraction limit of light conventional fluorescence microscopes are limited in their resolution to ~250 nm (approximately equal to half the wavelength of the used light beam). Nevertheless, cellular structures including synapses but especially the proteins they are composed of are far smaller, partially by more than a factor of 10. As a conventional fluorescent microscope illuminates all fluorophores within a spot at the same time, they also emit light at the same time. Therefore, two points in closer proximity than the full-width-half-maximum (FWHM) of their point spread function (PSF) will be difficult to resolve, as both PSF overlap to a certain degree. The invention of super-resolution microscopy broke the diffraction barrier within the last 20 years and opened a complete new field of science. In our lab we mainly use the super-resolution technique Stimulated Emission Depletion microscopy (STED).

For STED microscopy, two overlapping, synchronized laser beams are used, which arrive at the same sample position consecutively whereas the first laser excites the fluorophore (excitation laser) and forces an electron to a higher energy level whereas the second one (STED or depletion laser) de-excites/depletes it and forces the electron back to the ground state. In the region where both lasers are present, stimulated depletion is happening, while in a focal spot where just the excitations laser is present, spontaneous emission and therefore fluorescence is observed.

Electrophysiology

We use the Drosophila larval neuromuscular junction as a model to investigate neurotransmission. Here motoneurons innervate muscle cells forming a large number of synaptic connections. We insert sharp glass electrodes into larval muscles and measure the electrical properties of the membrane by making use of two different techniques:

Current clamp records changes in the membrane potential. Two electrode voltage clamp records the current injected to maintain a fixed holding potential of the muscle membrane. We investigate evoked neurotransmission by stimulating the presynaptic axon as well as spontaneous activity. We avail of different pharmacological agents to identify underlying mechanisms of synaptic function.

Computational Biology & Mathematical Modelling

Experimental Data is not always sufficient to fully understand the biological processes under investigation. Therefore, we employ computer-aided methods that help us build simulations and models of the synapse. Making assumptions about what processes are involved in a synaptic process, we formulate mathematical equations and have the computer solve them.

The simulations we derive from this can then be compared to experimental data. If our simulations do not agree with the experimental data, we know that we are making the wrong assumptions and can adapt the model until we find which underlying process we are missing.

 

 

 

Lab members

Name Title Job responsibilities Image
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Alexander Matthias Walter Associate Professor Billede af Alexander Matthias Walter
Danial Wasim Rana Laboratory Assistant Billede af Danial Wasim Rana
Maja Lill Elizabeth S Lützhøft Research Assistant Walther Lab Billede af Maja Lill Elizabeth S Lützhøft
Manon Monique Maria Berns PhD Fellow Walther Lab. Billede af Manon Monique Maria Berns
Mathias Böhme Postdoc Walter Lab Billede af Mathias Böhme
Natalie Blaum PhD Fellow Billede af Natalie Blaum
Paul Felix Fritz Guest Researcher Walter Lab Billede af Paul Felix Fritz