Metabotropic Glutamate Receptor-Mediated Neuromodulation in Sound Localization Circuits

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Project Summary Proper development of central auditory circuits depends on the patterned spontaneous activity originating in the cochlea (a peripheral mechanism). Disruption of this activity results in abnormal development of auditory circuits and compromised auditory processing and behavior. Our pilot work revealed that activation of metabotropic glutamate receptor 5 (mGluR5), one member of group I mGluRs, triggered patterned spontaneous activity in auditory brainstem neurons, implying a potential central mechanism underlying the spontaneous activity necessary for the development and maturation of auditory circuits. To fully understand the mechanism, we will examine in-depth the anatomy, physiology, and loss-of-function consequences of mGluR5 in the development of the brainstem sound localization (BSL) circuit in the mouse. Our central hypothesis is that mGluR5 is necessary for proper formation and function of the circuit, and dysfunctional mGluR5 leads to compromised neural properties underlying binaural processing. Specifically, we seek to determine: 1) the spatiotemporal pattern of mGluR5 expression; 2) the physiological functions of mGluR5; and 3) which developmental aspects of the circuit are disrupted if mGluR5 is eliminated. We hypothesize that: 1) mGluR5 expression is developmentally regulated; 2) mGluR5 modulates neuronal properties in the circuit; and 3) elimination of mGluR5 disrupts development of the BSL circuit. To test these hypotheses, we will use advanced anatomical analyses, in vitro physiology, optical imaging, immunohistochemistry, behavioral assessments, and genetic manipulations to pursue two specific aims. In Aim 1, we will investigate the anatomy and physiology of mGluR5 during development and into maturation. We will determine the cellular and subcellular localization of mGluR5, and then examine the modulatory functions of mGluR5 by testing our prediction that mGluR5 enhances intrinsic excitability and produces patterned spontaneous activity in the circuit. In Aim 2, we will investigate the mechanisms underlying malformation and malfunction of the circuit in genetically manipulated mice. By using the powerful Cre-loxP system (by crossing a neuron or astrocyte specific Cre mouse with a floxed mGluR5 mouse), we are able to eliminate mGluR5 exclusively on the glutamatergic pathways or in astrocytes. We predict that the elimination of mGluR5 compromises the core neuronal properties underlying the function of the circuit. Upon the successful completion of this project, we expect to obtain an in-depth understanding of mGluR5 neuromodulation in the development of the BSL circuit, providing a central mechanism underlying the patterned spontaneous activity critical for the development of auditory circuits. mGluR5 has been the target for drug development for treating numerous brain disorders. Our study will provide a foundation for pharmaceutical interventions that may prevent or rescue malformation and dysfunction of auditory circuits.