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.
