Eph-eprhin Signaling in Mapping Auditory Midbrain Circuitry

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DESCRIPTION (provided by applicant): The auditory system's functionally organized topographic maps preserve spatial representations and signal attributes received by the periphery. Tonotopic maps of best-frequency are the principal organizational feature exhibited by all auditory structures. Within layered tonotopic arrangements, secondary "nucleotopic" maps exist in mosaic form where discrete neuronal compartments or modules receive varying input arrays. Patterning and accurate alignment of these inputs define functional zones necessary for processing other stimulus features. Given the significance of topographic maps and the spatial precision necessary in defining functional auditory circuits, surprisingly little is known about th mechanisms that guide such connections early in development. We seek to determine the molecular mechanisms of pattern formation in the auditory midbrain, or inferior colliculus (IC), prior to experience. The IC receives numerous converging inputs terminating within a single topographical framework, making it an excellent model for studying targeting questions. Previous studies in our laboratory showed shaping of multiple afferent patterns in the central nucleus and lateral cortex of the IC (CNIC and LCIC, respectively) prior to hearing onset. We hypothesize that the spatial resolution necessary to establish this early topographic registry requires close cell-to-cell signaling via membrane- tethered guidance molecules. The Eph family of receptor tyrosine kinases, and their corresponding ligands, the ephrins, exhibit attractant (adhesive) or repulsive (de-adhesive) binding behaviors known to influence such spatially complex connection mapping . Recently, we reported graded and modular expression patterns (EphA4, ephrin-B2, and ephrin-B3 in CNIC and LCIC) that correlate temporally and spatially with segregating projection patterns. Utilizing established control (C57BL/6J) and Eph/ephrin mutant mouse colonies (EphA4lacZ, ephrin-B2lacZ, ephrin-B3lacZ, ephrin-B3-/-), the proposed work focuses on: layered inputs to the CNIC from the lateral superior olivary nuclei (LSO) and the dorsal nuclei of the lateral lemniscus (DNLL), as well as patterned inputs to the LCIC from the LSO and the CNIC. The planned experiments will test three hypotheses: 1) that topographic mapping errors occur in the CNIC and LCIC in Eph/ephrin-deficient mice, 2) that in vitro stripe assays reveal EphA4/ephrin-B2, -B3 signaling in the guidance of growing auditory axons, and 3) that altered topographic projections cause physiological (auditory brainstem responses, ABR) and behavioral (acoustic startle) effects in Eph/ephrin mutants. Understanding early guidance mechanisms in auditory networks will provide the foundation for assessing potential costs/benefits of stimulation paradigms, thus guiding new treatment strategies for the hearing impaired and those suffering from tinnitus. PUBLIC HEALTH RELEVANCE: Hearing, performed by the auditory system, is a vital sense and critical for speech and language acquisition. Despite significant incidences of hearing loss and innovative treatment strategies (e.g. implantation devices), fundamental questions remain unaddressed concerning auditory circuit development and organization. The goals of this project are to: 1) determine how a family of signaling molecules (Eph receptors and ephrins) guides patterned auditory circuit formation, 2) test their functional importance, and 3) apply mechanisms learned to fields of plasticity, recovery, and regeneration.