Project Summary Neuromodulation mediated by metabotropic glutamate receptors (mGluRs) regulates many brain functions. Dysfunction of mGluR modulation is associated with multiple brain disorders, and drugs targeting mGluRs have been developed for their treatment. However, the functions of mGluRs in the auditory system are poorly understood. In the absence of such knowledge, an understanding of the mechanisms underlying auditory processing and the potential to develop clinically useful strategies targeting mGluRs to prevent or treat hearing disorders will remain limited. The objective in this application is to determine the roles of mGluRs in the auditory brainstem circuit that analyze interaural time differences (ITD) for sound localization. Formulated based upon the previous work and strong preliminary data produced in the applicant's laboratory, the central hypotheses are that 1) mGluRs improve auditory processing by modulating synaptic and intrinsic neuronal properties; 2) hearing deprivation results in plasticity of mGluR modulation; and 3) dysfunctional mGluR modulation leads to compromised auditory processing. These hypotheses will be tested in both avian and mammalian models, utilizing the advantages of each animal model that are not prominent in the other. Furthermore, we will take advantage of a mouse model of fragile X syndrome (FXS), an inherited neurodevelopmental disorder in which exaggerated activity of mGluRs is the core underlying mechanism, to test the hypothesis that dysfunctional mGluR modulation contributes to compromised auditory processing. In vitro physiology (whole-cell and perforated patch recording and sharp electrode recording in brain slices), optical imaging (voltage-sensitive dye and Ca2+ imaging) combined with pharmacological tools, and immunohistochemistry will be used to determine the roles of mGluR modulation in the ITD circuit in normal hearing and hearing-deprived chicks, and in normal hearing and FXS mice. The successful completion of the proposed research will provide in-depth understanding of the roles of mGluRs in sound localization circuits, and may inform the identification of molecular targets for therapeutic intervention in hearing disorders.