Rutherford Lab

Sensory encoding and excitotoxicity

Principal Investigator:
Mark A. Rutherford, PhD, Assistant Professor, Otolaryngology-Head & Neck Surgery

Overview

The Rutherford Lab is focused on sensory encoding. We study how sound is transduced by the inner ear into action potentials in the auditory nerve through mechanisms of synaptic transmission.

During overexposure to sound, excessive release of glutamate from the sensory receptors (inner hair cells) drives an excitotoxic response that causes synaptic disintegration and auditory nerve degeneration. Our experiments are testing hypotheses about the mechanisms of glutamatergic excitotoxicity in the cochlea.

Auditory nerve fibers of the cochlea differ greatly in sound-response properties. In addition, they differ in excitotoxic vulnerability. Our overall goal is to know what makes them different, considering the combined effects of presynaptic, postsynaptic, and spike generator heterogeneities.

Research Projects

Relevance

Hearing loss is detrimental to the development of communication and behavioral skills, and detracts from quality of life. According to The Centers for Disease Control and Prevention and the National Institute on Deafness and Other Communication Disorders, 14.9% of children in the United States 6 to 19 years of age have significant hearing loss due to environmental factors or genetic diseases. Approximately 17% of Americans have some degree of hearing loss, predominantly due to noise exposure, and 47% of adults 75 years or older have a hearing loss due to normal exposure to sounds. These staggering statistics highlight the need for a better understanding of the protein mechanisms specifically important for hearing and the cellular processes that underlie use-dependent damage to the cells of the inner ear.

Goals

Cochlear hair cells and the auditory nerve fibers they excite have little to no capacity for regeneration, underscoring the need for proactive protection. We are learning about how to avoid damage to the specialized sensory receptors and nerve fibers of the inner ear. Sensory transduction is modulated by two efferent projections from the brainstem that impinge chemically on electro-mechanical mechanisms in the cochlea. Active processes amplify responses to soft sounds and suppress responses to loud sounds, enabling our sensitivity to sound pressure levels over six orders of magnitude. The efferent system modulates the gain of this sensitivity. In doing so, it exerts a putative protective influence even for moderate levels of sound. However, cochlear circuitry is poorly understood. A key physiological question is how the auditory periphery is modulated to protect against excitotoxicity while maintaining its extreme sensitivity. We are applying state-of-the-art research tools to define the normal mechanisms of cochlear function in order to explain and prevent disease. For example, a better understanding of efferent circuitry is expected to lead to therapies for prevention of hearing loss. Moreover, a more thorough understanding of afferent sensory encoding could produce better cochlear prosthetics for patients who can’t be helped by hearing aids. We seek to eventually understand the differences amongst individuals that predispose some of us to age-related and noise-induced hearing loss. This knowledge can ultimately be translated to patient care through personalized therapies, targeted to interact with individual genetic variations.

Research projects

  • Molecular anatomy of mammalian hair cell synapses will be elucidated to relate inner ear synaptic structure to afferent and efferent functions of hearing.
  • Mechanisms of synaptic transmission and action potential generation that underlie sensory encoding will be studied with state-of-the-art patch-clamp electrophysiology on sensory hair cells and auditory neurons.
  • The role of efferent neurotransmitters (e.g., dopamine) in membrane excitability and protection from noise-induced and age-related hearing loss will be investigated at the cellular level with structural and functional studies that utilize mammalian genetics.
  • Development of better cochlear prosthetics will be pursued using intracellular recording and cochlear implant-like stimulation of the auditory nerve. Collaborations within the excellent research environment at Washington University support these aims.

Lab Team

Mark A. Rutherford, PhD

Maolei Xiao, PhD

Babak V-Ghaffari, PhD

Shelby Payne

Heather Chung

Matt Nestor

Natalie Skigen

Jason Carlquist

Current Funding

2016-2021: NIDCD R01. Excitability and Excitotoxicity in Type I Cochlear Afferents: Synaptic Structure and Function.

2018-2019: Hearing Health Foundation, Fellowship Babak V-Ghaffari. Enhancing cochlear implant performance through development of improved auditory nerve fiber biophysical models with a combined wet lab and dry lab approach.

Select Publications

  1. Kyunghee X. Kim, Shelby Payne, Aizhen Yang-Hood, Song-Zhe Li, Bethany Davis, Jason Carlquist, Babak V-Ghaffari, Jay A. Gantz, Dorina Kallogjeri, James A. J. Fitzpatrick, Kevin K. Ohlemiller, Keiko Hirose, and Mark A. Rutherford. Vesicular Glutamatergic Transmission in Noise-induced Loss and Repair of Cochlear Ribbon Synapses. J Neurosci 2019 PMID: 30926748
  2. Choongheon Lee, John Guinan, Mark Rutherford, Wafaa Kaf, Kaitlyn Kennedy, Craig Buchman, Alec Salt, and Jeffery Lichtenhan. Cochlear compound action potentials from high-level tone bursts originate from wide cochlear regions that are offset toward the most sensitive cochlear region. JNeurophysiol 121(3): 1018 (2019). PMID: 30673362
  3. Becker, L., Schnee M.E., Niwa, M., Sun W., Maxeiner S., Talaei S., Kachar B., Rutherford M.A., and Ricci, A.J. The presynaptic ribbon maintains vesicle populations at the hair cell afferent fiber synapseeLife 7 (2018): e30241. PMID: 29328021
  4. Sebe, J.Y., Cho, S., Sheets, L., Rutherford, M.A., von Gersdorff, H., and Raible, D.W.  Ca2+-Permeable AMPARs Mediate Glutamatergic Transmission and Excitotoxic Damage at the Hair Cell Ribbon Synapse. The Journal of Neuroscience 37.25 (2017): 6162-6175. PMID: 28539424
  5. Hirose, K., Rutherford, M.A., and Warchol, M.E. Two cell populations participate in clearance of damaged hair cells from the sensory epithelia of the inner earHearing Research (2017). PMID: 28526177
  6. Ohn, T.L., Rutherford, M.A., Jing, Z., Jung, S., Duque-Afonso, C.J., Hoch, G., Picher, M.M., Scharinger, A., Strenzke, N., and Moser, T.  Hair Cells Use Active Zones with Different Voltage Dependence of Ca2+ Influx to Decompose Sounds into Complementary Neural Codes. PNAS 113(32): E4716 (2016) PMID: 2746210.
  7. Kim, Kyunghee X., and Mark A. Rutherford. “Maturation of NaV and KV Channel Topographies in the Auditory Nerve Spike Initiator before and after Developmental Onset of Hearing Function.” The Journal of Neuroscience 36.7 (2016): 2111-2118.
  8. Rutherford, M.A. and Moser, T. (2016)  “The Ribbon Synapse Between Type I Spiral Ganglion Neurons and Inner Hair Cells”  In: The Primary Auditory Neurons of the Mammalian Cochlea. Springer Handbook of Auditory Research. Eds. A. Dabdoub and B. Fritzsch. DOI 10.1007/978-1-4939-3031-9_5
  9. Rutherford, M.A. “Resolving the structure of inner ear ribbon synapses with STED microscopy.” Synapse 69.5 (2015): 242-255.
  10. Wong, A.B., Rutherford, M.A., Gabrielaitis, M., Pangršič, T., Göttfert, F., Frank, T., Michanski, F., Hell, S., Wolf, F., Wichman, C., Moser, T.  Developmental Refinement of Hair Cell Synapses Tightens the Coupling of Ca2+ Influx to Exocytosis. EMBO J 33(3):247 (2014). 
  11. Wong, A.B., Jing, Z., Rutherford, M.A., Frank, T., Strenzke, N., Moser, T. Concurrent Maturation of Inner Hair Cell Synaptic Ca2+ Influx and Auditory Nerve Spontaneous Activity around Hearing Onset in Mice. J Neurosci 33(26):10661 (2013). 
  12. Jing, Z., Rutherford, M.A., Takago, H., Frank, T., Fejtova, A., Khimich, D., Moser, T., Strenzke, N.  Disruption of the Presynaptic Cytomatrix Protein Bassoon Degrades Ribbon Anchorage, Multi-quantal Release, and Sound Encoding at the Hair Cell Afferent Synapse. J Neurosci 33(10):4456 (2013).
  13. von Ameln S, Wang G, Boulouiz R, Rutherford MA, Smith GM, Li Y, Pogoda HM, Nürnberg G, Volk AE, Stiller B, Hong JS, Goodyear RJ, Nürnberg P, Richardson GP, Hammerschmidt M, Moser T, Wollnik B, Koehler CM, Teitell MA, Barakat A, Kubisch C (2012) A Mutation in PNPT1, Encoding Mitochondrial-RNA-Import Protein PNPase, Causes Hereditary Hearing Loss.  Am J Hum Gen, 91(5):919-927.
  14. Rutherford MA, Pangršič T (2012) Molecular Anatomy and Physiology of Exocytosis in Sensory Hair Cells. Cell Calcium, 52(3-4):327-337.
  15. Rutherford MA, Chapochnikov NM, Moser T (2012) Spike Encoding of Neurotransmitter Release Timing by Spiral Ganglion Neurons of the Cochlea. J Neurosci, 32(14):4773-4789.
  16. Frank T, Rutherford MA, Strenzke N, Neef A, Pangršič T, Khimich D, Fetjova A, Gundelfinger ED, Liberman MC, Harke B, Bryan KE, Lee A, Egner A, Riedel D, Moser T (2010) Bassoon and the Synaptic Ribbon Organize Ca2+ Channels and Vesicles to Add Release Sites and Promote Refilling. Neuron, 68(4):724-738.
  17. Rutherford MA, Roberts WM (2009) Spikes and Membrane Potential Oscillations in Hair Cells Generate Periodic Afferent Activity in the Frog Sacculus. J Neurosci, 29(32):10025-10037.
  18. Roberts WM, Rutherford MA (2009) Linear and Nonlinear Processing in Hair Cells. J Exp Bio, 211(11):1775-1780.
  19. Rutherford MA, Roberts WM (2007) “Afferent Synaptic Mechanisms” In: The Senses: A Comprehensive Reference, Volume: Audition. Elsevier.
  20. Rutherford MA, Roberts WM (2006) Frequency Selectivity of Synaptic Exocytosis in Frog Saccular Hair Cells. Proc Natl Acad Sci USA, 103(8):2898-2903.

Contact Us

Mail address

Mark A. Rutherford
Dept. Otolaryngology, Campus Box 8115
Washington Univ. School of Medicine
660 So. Euclid Ave.
St. Louis, MO 63110
mrutherford at wustl.edu


Physical address

CID Building
Room 2215 (lab), 2278 (office)
4560 Clayton Ave.
St. Louis, MO 63110


lab phone: (314) 747-7152
office phone: (314) 747-7160
fax: (314) 362-1618