Mechanisms Regulating Synaptic Function in the Developing Auditory System



 DESCRIPTION (provided by applicant): The goal of this research is to identify mechanisms that give rise to fast neural encoding of sound critical for normal auditory function. However, developmental mechanisms are poorly understood in the brainstem, where deficits in fast neural encoding underlie aspects of auditory temporal processing disorders. At mature auditory synapses, fast neural encoding is mediated by AMPA-type glutamate receptors (AMPA-Rs) due largely in part to their subunit arrangement, which is distinct from other brain regions. Their unique subunit arrangement raises important biological questions: are the mechanisms that regulate the development of specialized AMPA- R properties in the auditory system similar to mechanisms that regulate AMPA-Rs elsewhere in the brain? If so, what mechanisms govern this different arrangement of AMPA-R subunits? If not, are alternative mechanisms regulating AMPA-Rs exclusive to the auditory system? This study will address these questions by investigating the regulation of synaptic AMPA-Rs properties in the avian auditory brainstem. Elsewhere in the developing brain, NMDA-Rs assist in regulating normal AMPA-R properties and during specific diseased states; NMDA-Rs are implicated as a molecular target in controlling synaptic AMPA-R dysfunction. NMDA-Rs also play a negative role in diseases of the auditory system, including tinnitus, noise- induced hearing loss and neural presbycusis. However, the causal role NMDA-Rs plays in regulating synaptic AMPA-Rs and the extent to which they contribute to fast neural encoding of sound in the developing auditory brainstem are not known. This study will test the hypothesis that the establishment of fast neural encoding requires NMDA-R dependent regulation of synaptic AMPA-R properties in the developing brainstem, critical for precise auditory temporal processing abilities. Investigating the regulator role of NMDA-Rs on AMPA-Rs will be a significant first step in understanding pathologies associated with auditory temporal processing disorders. Using innovative methods, the project aims to determine the extent to which NMDA-Rs (1) regulate the number and subunit composition of synaptic AMPA-R in the developing avian nucleus magnocellularis (NM) and (2) to determine the extent to which temporal speed and precision are mediated by AMPA-Rs at functionally mature NM synapses following genetic manipulation of NMDA-Rs. I will combine in-ovo genetic manipulations, pharmacological/biochemical assays, and in-vitro patch clamp electrophysiology to test the above Aims during developmental time periods corresponding to synapse formation, hearing onset, and functional maturation. Gaining an understanding of NMDA-Rs contribution to synaptic development and refinement should shed light on the role of subunit-specific AMPA-Rs in the auditory system. A better understanding of molecular-level NMDA-R mechanisms may identify pharmacological targets to improve disorders in which synaptic AMPA-R dysfunction has either a direct or causal role in pathologies related to auditory temporal processing.