We have known for decades that glutamate receptors mediate synaptic transmission between the inner hair cell and its afferent fiber, yet we know astonishingly little about the contributions of the different types of glutamate receptors to stimulus coding and auditory pathology. All 4 basic types of glutamate receptors (AMPA, kainate, metabotropic, and NMDA) are present on afferent terminals but the only one we really understand well is the AMPA receptor, which mediates moment-by-moment transmission at this synapse. Understanding how these different types of glutamate receptors interact to code acoustic signals will illuminate how this synapse achieves some of its extraordinary information transfer capabilities and how its failure modes can lead to excitotoxic hearing loss.
The specific aims are:
Aim 1 : How do different glutamate receptors cooperate to produce sound-evoked responses in the cochlea? Aim 2. Test the hypothesis that kainate receptors are trafficked and regulated at the hair cell synapse.
Aim 3 : How do different glutamate receptors contribute to excitotoxicity in the cochlea? Understanding the roles of these receptors in cochlear function could also lead to strategies to improve hearing. For example, a greater understanding of the role NMDA receptors play in the cochlea could lead to new tinnitus therapies. Understanding trafficking could lead to drugs that improve hearing by increasing the sensitivity of afferent neurons to auditory stimuli. Knowledge of the roles that the different neurotransmitters play in cochlear function could help in developing strategies for reinnervating hair cells in future therapies based on regenerating hair cells. Finally, understanding the roles of these different glutamate receptors at the hair cell afferent synapse provides an extraordinary opportunity to understand fundamental issues of glutamate receptor coding with relevance to understanding synaptic function in the nervous system in general. The simplicity and extreme organization of the innervation pattern in the cochlea, coupled to the ability to precisely deliver sensory signals and monitor responses while perfusing the synapse with drugs allows us to precisely address the roles of these receptors in signal processing in vivo.
Understanding the roles of the different glutamate receptors in cochlear function and pathology (1) will open new approaches to treating auditory neuropathies and (2) can lead to strategies to pharmacologically enhance responsiveness of the glutamate receptor to improve hearing. (3) A greater understanding of the role NMDA receptors play in the cochlea could lead to new tinnitus therapies. (4) Knowledge of the roles that the different neurotransmitters play in cochlear function could help in developing strategies for reinnervating hair cells in future therapies based on regenerating hair cells.
| Sebe, Joy Y; Cho, Soyoun; Sheets, Lavinia et al. (2017) Ca2+-Permeable AMPARs Mediate Glutamatergic Transmission and Excitotoxic Damage at the Hair Cell Ribbon Synapse. J Neurosci 37:6162-6175 |
| Sheets, Lavinia (2017) Excessive activation of ionotropic glutamate receptors induces apoptotic hair-cell death independent of afferent and efferent innervation. Sci Rep 7:41102 |
