Uncovering the Functional Effects of Neurotrophins in the Auditory Brainstem

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PROJECT SUMMARY/ABSTRACT Neurotrophins are secreted signaling proteins that promote the growth and organization of developing neurons. Gradients of expression of the neurotrophin and its associated tyrosine receptor kinase (Trk) allow for spatiotemporally regulated signaling that promotes synapse strengthening and neuronal maturation. For example, Brain-derived neurotrophic factor (BDNF) is a neurotrophin that is secreted within the developing avian auditory brainstem. Its receptor, tryrosine receptor kinase B (TrkB), is highly expressed early in embryonic development and systematically decreases to negligible amount by the time the embryo hatches. While neurotrophin signaling is essential to induce cellular and synaptic maturation in other neural tissues, its direct effects on the development and functionality of the central auditory system remains unknown. Temporal precision is essential for auditory brainstem neurons to accurately encode the complexities of sound. Therefore, the objective of this research proposal is to determine how neurotrophin signaling affects intrinsic ion channel properties responsible for establishing functional phenotypes for the roles they subserve: binaural hearing and sound localization. Specifically, I will investigate the role of the BDNF/TrkB signaling pathway on defining the intrinsic phenotype of auditory brainstem neurons. I will additionally test the importance of neurotrophin regulation on the development of mature and robust auditory brainstem signaling in response to sound. The central hypothesis of this research proposal is that altered neurotrophin signaling in the auditory brainstem will decrease the ability for auditory brainstem neurons to transmit information in a temporally reliable manner. In Aim 1 I will use patch clamp electrophysiology to determine the effects of aberrant neurotrophin signaling on the intrinsic properties of auditory brainstem neurons. In Aim 2 I will assess the functional ramifications of irregular neurotrophin signaling by measuring electrical field potentials from auditory brainstem structures. Collectively, this research will elucidate the importance of neurotrophin signaling at the cellular and systems level within the auditory brainstem, providing possible candidates for developmental signals that may be dysregulated in early central auditory-related disorders.