Tobias Moser on Studying Sound Coding at the Cochlear Hair Cell Synapse

Scientist Interview: June 2011

Tobias MoserAccording to a recent analysis of Essential Science IndicatorsSM data from Thomson Reuters, the work of Prof. Dr. Tobias Moser had the highest percent increase in total citations in the field of Neuroscience & Behavior. His current record in this field includes 25 papers cited a total of 923 times between January 1, 2001 and February 28, 2011. He also has papers in Biology & Biochemistry, Clinical Medicine, and Molecular Biology & Genetics.

In the Web of Science®, his record includes 45 papers cited a total of 1,359 times between January 1, 2001 and May 22, 2011.

Moser is Professor of Auditory Neuroscience in the InnerEarLab of the Department of Otolaryngology of Göttingen University Medical Center and co-affiliated with the Center for Molecular Physiology of the Brain and the Bernstein Center for Computational Neuroscience at the University of Göttingen, Germany.

Below, he talks with about his highly cited work in Neuroscience & Behavior.

SW: Please tell us about your educational background and research experiences.

I received medical training at the Universities of Leipzig and Jena, Germany. Bernd Nilius (now Leuven, Belgium) and then Erwin Neher (Göttingen, Germany) trained me in cell physiology/biophysics. Experiments performed during research stays in Göttingen in parallel to the medical training led to a medical thesis. I then decided on postdoctoral research training and had the great opportunity to continue work on exocytosis of neuroendocrine cells under Erwin Neher's guidance in Göttingen.

During this period I characterized the secretory behavior of chromaffin cells in tissue slices and together with colleagues contributed to better understanding the regulation of chromaffin cell exocytosis by calcium and the proteins synaptotagmin 1 and munc18-1. In searching for a more independent research profile I became interested in sensory hair cells as technically accessible presynaptic cells. I was attracted by their essential role in a tractable sensory system and the implications of dysfunction in human deafness.

CDKs and the cell cycle. Schematic representation of some of the mammalian CDKs involved in progression throughout the different phases of the cell cycle. Some of these kinases are required for DNA replication (S-phase) whereas other participate in the preparation for chromosome segregation during mitosis. Their therapeutic validation, however, requires proper analysis of this basic version of the cell cycle in different cell types and under different oncogenic backgrounds in vivo.
Tobias Moser... at work or at play? View more images at the InnerEarLab, Department of Otolaryngology and Center for Molecular Physiology of the Brain Picture Gallery.

To better understand the system and the clinical aspects I performed a five-year residency in otorhinolaryngology at Göttingen University School of Medicine, while building my group for research on hair cell presynaptic physiology. I was very lucky in having two mentors: Erwin Neher and Wolfgang Steiner (Chairman of the Department of Otorhinolaryngology) who supported this career. I also received help from Dominik Oliver (now Professor of Physiology in Marburg, Germany) in setting up the cochlear microdissection.

SW: What first drew you to the neurosciences? Is there a specific area within this field on which you focus, or do you maintain a wide variety of interests?

I was attracted by synaptic neuroscience/biophysics as an interesting, technically advanced and still growing field. I try to follow my interest in understanding the molecular and cellular mechanisms governing exo- and endocytosis. However, studying how a particular synapse works in the systems context and how its dysfunction affects the system has become more and more important for me and my colleagues.

To understand how the hair cell ribbon synapse achieves submillisecond precision of sound coding and sustains release rates of hundreds of vesicles per seconds over prolonged periods of time is a daunting task, which is pursued by a number of excellent groups world-wide. We and others have realized that in order to progress in this matter we need to approach synaptic sound encoding from several sides involving various techniques such as genetics, molecular and structural biology, and biochemistry as well as morphology and physiology at various levels.

The hair cell synapses offer advantages (accessibility to in vitro and in vivo physiology) and have disadvantages (little biological material). The link to human disease has been a strong help and motivation for us: some of the genes (e.g., Otof coding for otoferlin, a C2-domain protein essential for hair cell exocytosis and hearing) have been identified by human genetics, and the devastating hearing impairment of auditory synaptopathy demonstrates the relevance of understanding sound coding and devising potential therapeutic concepts.

This way we find ourselves connected to different scientific fields, e.g., general synaptic biophysics, auditory neuroscience, computational neuroscience, optogenetics, and clinical audiology. So yes, we focus on studying sound coding at the hair cell synapse but approach it by various techniques and on different levels of observation.

SW: Several of your highly cited papers deal with cochlear hair cells and/or calcium channels. Would you talk about this aspect of your research? What's the connection between the two? What’s the significance?

As stated before, cochlear hair cells are experts in presynaptic transmitter release and hence employ highly sophisticated synapses. For example: for as long as we listen to a symphony concert, hair cell synapses need to display activatable calcium channels and synaptic vesicles that can undergo calcium-triggered exocytosis. So we can listen for the entire length of the concert, because hair cells utilize calcium channels that show very little inactivation and have very efficient vesicle replenishment.

The hair cell calcium channels are very special: L-type (a1d/Cav1.3 and Cavß2) that are modulated by a number of interacting proteins conferring to them their specific properties. Also, it seems that the synapses use a unique set of synaptic proteins, such as the multi-C2 domain protein otoferlin, that seems rather specific to the hair cells and is required for efficient vesicle replenishment and probably for fusion. Finally, their active zone features an electron-dense structure, the synaptic ribbon, tethering a number of synaptic vesicles.

"…we focus on studying sound coding at the hair cell synapse but approach it by various techniques and on different levels of observation."

The function of this "nanomachine" is still debated, but there is emerging evidence for it to stabilize the vesicle docking and calcium channel clustering at their large active zones. Moreover, it is thought to be involved in vesicle replenishment. We think that calcium channel(s) and membrane-tethered vesicles, together, form "functional units" or "release sites" wherein the calcium triggering the vesicle fusion is under the control of one or a few open channels in nanometer proximity.

Considering a Beethoven symphony, we need our hair cell synapses to deal with an impressive dynamic range of sound intensities. It turns out that the individual neurons forming our auditory nerve differ largely in their sensitivity and dynamic range and, hence, may play as a team in order to provide the brain with information on the entire dynamic range of acoustic stimuli.

Interestingly, classical work by Charles Liberman and others suggests that each hair cell "drives" fibers of all types. How then can they be so different? Based on studies of the calcium signals of the different synapses of the individual hair cell, we argue that the synapses of an individual hair cell differ in their presynaptic complement of calcium channels. We found a pronounced heterogeneity of synapses with regard to voltage dependence of the calcium microdomain and to the calcium microdomain amplitude at saturating depolarization.

SW: What would you say is the ultimate goal or benefit of this work?

Understanding sound encoding at the hair cell synapse and its synaptopathic failure. Gene-therapy to hair cell synaptopathies as well as refinement of cochlear prosthetics using optogenetics.

SW: Are there any projects you have forthcoming that you are free to discuss?

We are still only at the beginning of understanding the molecular anatomy and physiology of these fascinating synapses. Ongoing work involves studies of the function of synaptic proteins and protein complexes at the hair cell synapse and of the mechanisms underlying synaptic heterogeneity. In addition we approach the foundations of gene therapy of synaptopathies and work on developing an optogenetic cochlear implant for improved resolution of sound frequency coding.

SW:  In what directions do you see your field (or key aspects thereof) going in the next decade?

The field of hair cell synaptic transmission is an exciting and growing one involving a number of excellent groups. Studies will likely address the molecular anatomy and physiology with more and more refined methods such as paired pre- and postsynaptic recordings, optical imaging of calcium signals and exocytosis as well as morphology using state-of-the-art light and electron microscopy. Genetics, protein biochemistry, mass spectrometry, and "in cell" interaction studies will help to decipher the interactome of synaptic proteins and calcium channels. Work will also involve systems-level and behavioral analysis of the consequences of a specific genetic manipulation of the hair cell synapse.End

Tobias Moser, M.D.
Department of Otolaryngology
Center for Molecular Physiology of the Brain
Bernstein Center for Computational Neuroscience
University of Göttingen
Göttingen, Germany

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