Professor, Departments of Molecular and Human Genetics and Neuroscience

State licensed Pharmacist, Goethe University Frankfurt, Germany, 1989
Ph.D., Physiology, Vollum Institute, Oregon Health Sciences University, Portland, Oregon, 1993
Lecturer in Physiology, Goettingen University, Germany, 1999
Group leader, Department of Membrane Biophysics, Max-Planck-Institute for Biophysical Chemistry, 1998-2003

RESEARCH INTERESTS:

When action potentials reach the synapse the electrical signal is transduced into a chemical via release of neurotransmitters, in turn activating postsynaptic receptors and altering the postsynaptic membrane potential. How this transduction process works and how it shapes, and is shaped by, the information it encodes is not well understood. We take a “reverse engineering” approach to dissect this transduction machinery. This involves taking essential proteins of the synapses “apart” and analyzing their workings in a highly quantifiable manner. Our specific questions focus on how synaptic vesicles get ready to become fusion competent, and how Ca²⁺ triggers the fusion event. To elucidate the molecular mechanisms, we use a multidisciplinary approach with particular emphasis on electrophysiology and imaging, quantitative analysis, and collaborate worldwide with biochemists, geneticists, and structural biologists.

Essential to our current functional analysis of the presynapse is the single neuron culture from mice. This preparation allows us to easily record synaptic activity while maintaining optimal control of the neuronal environment and providing excellent optical access. To characterize the function of essential proteins in synaptic transmission, we use a combination of loss-of-function and gain-of-function-rescue approaches. We first use knockout mice to define the general function of a protein by associating the phenotype to a specific step in the release process. We then use lentiviral overexpression of wildtype and mutant versions in neurons from knockout mice. This allows an in-depth analysis of protein function to reveal the role of structurally or biochemically defined protein domains and protein-protein interactions. Current projects include:

Vesicular Neurotransmitter Transporters (VGLUTs) accumulate glutamate in synaptic vesicles. In mammalian synapses, the average VGLUT copy number per vesicle is 10, however, VGLUT copy number on vesicles likely varies, as VGLUT expression levels in neurons change dramatically during development, in disease states or during synaptic plasticity. We found that both the VGLUT copy number as well as which of the three VGLUT paralogs is expressed in a given synapse, profoundly affects synaptic strength. We are currently studying how VGLUTs regulate synaptic strength, and how this is utilized in the nervous system.

Munc13, Vesicle Priming and Its Role in Short Term Plasticity: Vesicles need to be primed to reach fusion competence. Among individual primed vesicles, the probability of vesicle release can vary over more than an order of magnitude, and we are particularly interested in modulatory factors such as Munc13s. Synapses lacking Munc13 show vesicle docking to the plasma mebrane, but no vesicle release. However, Munc13 also regulates vesicle release probability through an activity dependent intramolecular conformational switch that dynamically regulates the energy barrier for vesicle fusion. We study this mechanisms now in more detail using electrophysiology, site directed mutagenesis and molecular imaging techniques (Fig. 1).

Ca²⁺ Triggered Release: Postsynaptic responses must be “in sync” with the presynaptic spike pattern to ensure optimal use of the neuronal code. We are currently studying two proteins that enable synchronous release: the vesicular protein synaptotagmin 1 (syt) and the Complexins (CPX). We are interested how Complexins and syt enable synchronous release (Fig. 2) using both structure function approaches as well as through genetic interaction studies.

SELECTED PUBLICATIONS:

1. Basu J, Betz A, Brose N, Rosenmund C (2007). Munc13-1 C1 domain activation lowers the energy barrier for synaptic vesicle fusion. J. Neurosci. 27: 1200-1210.

2. Weston MC, Gertler C, Mayer ML, Rosenmund C (2006). Interdomain interactions in AMPA and kainate receptors regulate affinity for glutamate. J. Neurosci. 26: 7650-7658.

3. Schluter OM, Basu J, Sudhof TC, Rosenmund C (2006). Rab3 superprimes synaptic vesicles for release: implications for short-term synaptic plasticity. J. Neurosci. 26: 1239-1246.

4. Rhee JS, Li LY, Shin OH, Rah JC, Rizo J, Sudhof TC, Rosenmund C (2005). Augmenting neurotransmitter release by enhancing the apparent Ca²⁺ affinity of synaptotagmin 1. Proc. Natl. Acad. Sci. USA 102: 18664-18669.

5. Rosenmund C, Rettig J, Brose N (2004). Molecular mechanisms of active zone function. Curr. Opin. Neurobiol. 13: 509-519.

6. Wojcik SM, Rhee JS, Herzog E, Sigler A, Jahn R, Takamori S, Brose N, Rosenmund C (2004). An essential role for vesicular glutamate transporter 1 (VGLUT1) in postnatal development and control of quantal size. Proc. Natl. Acad. Sci. USA 101: 7158-7163.

7. Varoqueaux F, Sigler A, Rhee JS, Brose N, Enk C, Reim K, Rosenmund C (2002). Total arrest of spontaneous and evoked synaptic transmission but normal synaptogenesis in the absence of Munc13-mediated vesicle priming. Proc. Natl. Acad. Sci. USA 99: 9037-9042.

8. Rosenmund C, Sigler A, Augustin I, Reim K, Brose N, Rhee JS (2002). Differential control of vesicle priming and short term plasticity by Munc13 isoforms. Neuron 33: 411-424.

9. Reim K, Mansour M, Varoqueaux F, McMahon HT, Südhof TC, Brose N, Rosenmund C (2001). Complexins regulate a late step in Ca²⁺-dependent neurotransmitter release. Cell 104: 71-81.

10. Fernandez-Chacon R, Konigstorfer A, Gerber SH, Garcia J, Matos MF, Stevens CF, Brose N, Rizo J, Rosenmund C, Sudhof TC (2001). Synaptotagmin I functions as a calcium regulator of release probability. Nature 410: 41-49.

For more publications, see listing on Pub Med.

CONTACT INFORMATION:

Christian Rosenmund, Ph.D.
Department of Molecular and Human Genetics
Baylor College of Medicine
One Baylor Plaza, MS BCM225
Houston, TX, 77030, U.S.A.

Phone: 713-798-9022
Fax: 713-798-2027
E-mail:

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