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 AG Martin Schwarz

 

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Personal Statement


I received my PhD in 1998 in Vienna, for my work performed at the Max-Planck Institute for Biophysical Chemistry in Göttingen-Germany.  Under the guidance of Prof. Peter Gruss, I identified genes responsible for early brain regionalization and thus acquired fundamental training in brain development and brain anatomy.  My work was judged as “fundamentally important for the field of developmental biology” and consequently honored with the “Otto-Hahn Medal”. This price is awarded by the Max-Planck Society and honors the best graduate research performed in any Max-Planck Institute during the preceding year.  

After the completion of my PhD, I moved to the Max-Planck Institute for Medical Research in Heidelberg to join Prof. Peter Seeburg’s department. In Heidelberg, I focused my efforts on molecular neuroscience to address how postsynaptic proteins regulate the function of ionotropic glutamate receptors. This postdoctoral work resulted in identification and characterization of the Homer1 gene locus, generation of transgenic and knock-out mouse lines and a very detailed identification of postsynaptic molecular dynamics. Moreover I had the chance to pioneer, together with the group of Prof. Matthias Klugmann, recombinant adeno-associated viruses as versatile tools to study neuronal functions in mice.

From 2006 on, I was leading my own research group at the Max-Planck Institute for Medical Research in Heidelberg as principal investigator (PI).  During that time, my research initially focused on the functional characterization of clustered protocadherins, genes involved in neuronal wiring specificity, and the development of novel molecular methods to anatomically trace and functionally dissect neural circuits with a special emphasis to the olfactory system and the hippocampus (“functional neuroconnectomics”).  My group successfully established and further developed molecular methods allowing the identification of synaptically connected neuronal networks in a quantitative manner (rabies virus-mediated mono-transsynaptic tracing). For the analysis of these neuronal networks, my research group developed, in close collaboration with the Department of Prof. Winfried Denk, a brain clearing method (FluoClearBABB) allowing me to analyze fluorescently labeled neuronal networks with a purpose built light-sheet fluorescence microscope. These developments lead to the discovery of unknown neuronal circuits motifs involved in olfactory driven social recognition.

Having developed key technologies in neuroconnectomics, my lab moved beginning of 2014 to the University of Bonn, Medical Faculty, where I joined the newly established SFB 1089 “Synaptic micronetworks in health and disease” as the PI of the newly established “Functional Neuroconnectomics Group”. In Bonn, I am closely affiliated with the department of Epileptology, one of the world-wide leading institutions in epilepsy treatment and research. This great scientific environment offered the unique possibility to combine my knowledge in neuroconnectomics with the expert knowledge of neurophysiologists investigating molecular and cellular aspects of epilepsy. Due to my expertise in viral technologies, tissue clearing procedures and light sheet fluorescence microscope imaging I became also affiliated with the Life &Brain Center in Bonn, where I am working in collaboration with the Department of Prof. Oliver Brüstle, with whom I built a light sheet fluorescence microscope for the imaging of large, cleared tissue samples.

Lastly, I would like to point out that my experience and qualifications, as documented by my publications, not only underline my long-standing experience in brain anatomy, physiology and the development of novel methods to study neuroconnectomics, but also outline my collaborative personality.

 

 

Contribution to Science


Early mammalian brain regionalization (reciprocal transcriptional repression)


Paired  box-containing  (Pax) transcription factors are critical regulators of early brain regionalization. I was critically involved in the characterization of the molecular cascades driven by Pax genes that dictate the early regionalization of the mammalian brain. In a landmark study I could demonstrate that the two transcription factors Pax2 and Pax6 establish the mid-hindbrain-, as well as the optic stalc to optic cup boundary by a novel mechanism called reciprocal transcriptional repression.

 

Key publications

 

  1. Schwarz, M.K., Cecconi, F., Bernier, G., Andrejewski, A., Kammandel, B., Wagner, M., Gruss, P. Spatial specification of mammalian eye territories by reciprocal transcriptional repression of Pax2 and Pax6. Development. (2000),127:4325-4334.
  2. Schwarz, M.K., Alvarez-Bolado, G., Urbanek, P., Dressler, G., Busslinger, M., Gruss, P. Pax2/5 and Pax6 subdivide the early neural tube into three domains. Mechanisms of Development. (1999),82:1-9.
  3. Schwarz,  M.K., Alvarez-Bolado,  G., Urbanek, P., Busslinger, M., Gruss, P. Conserved biological function between Pax2 and Pax5 in midbrain and cerebellum development: Evidence from targeted mutations. PNAS. (1997),94:14518-14523.
  4. Alvarez-Bolado, G., Schwarz, M.K., Gruss, P. Pax-2 in the chiasm. Cell and Tissue Research. (1997),290:197-200.

 

Molecular constituents of synaptic specificity


The genomic architecture of the protocadherin gene clusters is analogous to that of the immunglobulin T cell receptor gene cluster, and thus can potentially provide the molecular diversity required for establishment and maintenance of complex neural networks in the brain. The N-terminal extracellular and transmembrane domains of each protocadherin are encoded by a distinct and unusually large exon. By contrast, the C-terminal cytoplasmic domain of each  protocadherin is identical and is encoded by three small exons located downstream from each cluster of N-terminal exons. Regardless of the high number of different adhesive protocadherin combinations which can be generated, the function of the conserved intracellular domain remained elusive. I designed and conducted the first experiments that elucidated different aspects of protocadherin intracellular signaling function.

 

Key publications

 

  1. Bonn, S., Seeburg, P.H., Schwarz, M.K. Combinatorial expression of alpha- and gamma-Protocadherins alters their presenilin-dependent processing. MCB. (2007),27(11):4121-32.
  2. Hambsch, B., Grinevich, V., Seeburg, P.H., Schwarz, M.K. Gamma-Protocadherins: presenilin-mediated release of c-terminal fragment promotes locus expression. JBC. (2005),22:15888-97.
  3. Vites, O., Rhee, J.-S., Schwarz, M.K., Rosenmund, C., Jahn, R. Reinvestigation of the role of Snapin in neurotransmitter release. JBC. (2004),25:26251-26256.

 

Neuronal immediate early genes


Spatial localization and clustering of membrane proteins is critical to neuronal development and synaptic plasticity. The expression of Homer1a, a dendritic protein, is regulated as a neuronal immediate early gene and is dynamically responsive to physiological synaptic activity, particularly during cortical development. I was substantially involved in extrapolating the wealth of in vitro data on Homer proteins to the whole animal. Towards this end I have conducted the first analysis of the genomic organization of the Homer 1 gene locus,  the first knock-out of the Homer 1 gene and its immediate early gene form Homer 1a, and studied  the function of the Homer1a in learning and memory formation.

 

Key publications

 

  1. Yuan, J.P., Kiselyov, K., Shin, D.M., Chen, J., Shcheynikov, N., Kang, S., Dehoff, M.H., Schwarz, M.K., Seeburg, P.H., Mullaem, S., Worley, P.F. Homer binds TRPC family channels and is required for gating of TRPC1 by IP3 receptors. Cell. (2003),114;777-789.
  2. Hu, J.H., Park, J.M., Park, S., Xiao, B., Dehoff, M.H., Kim, S., Hayashi, T., Schwarz, M.K., Huganir, R.L., Seeburg, P.H., Linden, D.J., Worley, P.F. Homeostatic scaling requires group I mGluR activation mediated by Homer1a. Neuron. (2010),68(6):1128-42.
  3. Celikel, T., Marx, V., Zivkovic, A., Rozov, A., Licznerski, P., Osten, P., Hasan, M., Seeburg P.H., Schwarz M.K.Select overexpression of Homer 1a in dorsal hippocampus impairs spatial working memory. Frontiers in Neuroscience. (2007),1:97-110.
  4. Rozov, A., Zivkovic., A., Schwarz, M. K.Homer1 gene products orchestrate Ca2+-permeable AMPA receptor distribution and LTP expression. Frontiers in Neuroscience. (2012),4:1-10.

 

Light sheet fluorescent microscopy, tissue clearing and neural circuit analysis


In imaging there is usually a compromise between volume and resolution. In general, large volumes can only be imaged with low spatial resolution, while high spatial resolution is accomplished only over small volumes. This limitation is especially problematic in nervous tissue, where synaptically connected neurons can be spatially separated over very long distances and in three dimensions. Critical details of neuronal connectivity occur at the subcellular level of neurites (axons and dendrites), structures that cannot be easily imaged in the context of extended neuronal networks in high resolution. I have realized large volume network imaging of nervous tissue in high resolution by combining virus-based transsynaptic tracing methods with novel tissue clearing protocols and high-resolution light sheet fluorescence microscopy imaging. Using this technique I achieved the first quantitative connectivity maps of the olfactory system as well as the hippocampal formation. My procedure promise to significantly contribute to the body of work that aims to better understand in detail the connectivity matrix of complex neuronal circuits, that underlie health and disease and is an important continuing focus in my lab.

 

Key publications

 

  1. Schmid, LC., Mittag, M., Steffen, J., Wagner, J., Geis, HR., Schwarz, I., Schmidt, B., Schwarz, MK., Remy, S., Fuhrmann, M. Dysfunction of Somatostatin-Positive Interneurons in an Alzheimer’s Disease Model. Neuron in press
  2. Meye, FJ., Soiza-Reilly, M., Smit, T., Diana, MA., Schwarz, MK., Mameli, M. Shifted pallidal co-release of GABA and glutamate in habenular drives cocaine withdrawal and relapse. Nature Neuroscience (2016), 19(8):1019-1027
  3. Fuhrmann, F., Justus, D., Sosulina, L., Kaneko, H., Beutel, T., Friedrichs, D., Schoch, S., Schwarz, K.M., Fuhrmann, M., Remy, S. Locomotion, Theta Oscillations, and Speed-Correlated Firing of Hippocampal Neurons Are Controlled by a Medial Septal Glutamatergic Circuit. Neuron. (2015), 86(5): 1245-1264
  4. Schwarz, M. K., Scherbarth, A., Sprengel, R., Engelhardt, J., Theer, P., Giese, G. Fluorescent-Protein Stabilization and High-Resolution Imaging of Cleared, Intact Mouse Brains. PlosOne. (2015), DOI:10.1371
  5. Niedworok, C., Schwarz, I., Ledderose, J., Giese, G., Conzelmann, K.K., Schwarz, M.K. Charting olfactory connectivity maps by two-color light-sheet fluorescence microscopy. Cell Reports. (2012),2(5):1375-86.
  6. Rancz, E.A., Franks, K.M., Schwarz, M.K., Pichler, B., Schaefer, A., Margrie, T.W. Transfection via whole-cell recording in vivo: bridging single-cell physiology, genetics and connectomics. Nat. Neuroscience. (2011),14(4): 527-32.
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