G-protein-coupled Receptors in Hearing Physiology

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DESCRIPTION (provided by applicant): Hearing defects are a significant societal problem in that they interfere with language development, education, and quality of life. Many defects result from dysfunctional central nervous system processing of auditory signals. G-protein-coupled receptors (GPCRs), the largest family of transmembrane proteins, are widespread and play important roles in the nervous system. Moreover, GPCRs are major common targets for new drug development. The long-term goal of this research is to understand the role of GPCRs associated with the two most prominent neurotransmitters, glutamate and GABA, in temporal processing in the auditory system, an important process that helps us to recognize and localize complex acoustic signals such as speech. Glutamate interacts with metabotropic glutamate receptors (mGluRs), and GABA with GABAB receptors (GABABRs), both of which are GPCRs. When activated, these receptors initiate a multitude of signaling transduction pathways important in mediating modulation of neuronal excitability and synaptic transmission (one of the major ways cells communicate with each other). Functions of these receptors in the auditory system are not well understood; this hinders drug development for treating hearing problems targeting these receptors. The primary focus of the present proposal is to determine how glutamate/mGluRs and GABA/GABABRs are involved in modulating synaptic transmission in auditory brainstem neurons that code temporal information of sounds. Our overall hypothesis is that mGluRs and GABABRs improve temporal processing in auditory brainstem neurons. We will use electrophysiological approaches (e.g., whole-cell and/or perforated patch recordings) combined with pharmacological tools (e.g. chemical agents that activate or suppress mGluRs and/or GABABRs) in acute brain slice preparations. Mechanisms whereby these receptors improve temporal processing in hearing will be revealed at cellular and molecular levels. The results of this work will further our understanding of how metabotropic receptors contribute to auditory signal processing/temporal coding, and help lay the groundwork for decisions about possible therapeutic approaches to hearing defects related to altered synaptic transmission, such as dyslexia, tinnitus, and age-related hearing loss.