Regulation of exo- and endocytosis at ribbon synapses of auditory hair cells

Oregon Health & Science University, Portland OR

Investigators

Abstract

DESCRIPTION (provided by applicant): Perception of the external world begins with transduction of physical stimuli into biochemical signals by receptor neurons. To propagate these signals throughout the nervous system, receptor neurons in both the auditory and visual information pathways of vertebrates employ specialized synapses characterized by a dense presynaptic structure known as a ribbon. Synaptic ribbons possess unique features thought to facilitate sustained, low-latency exocytosis of neurotransmitter in response to activation of the presynaptic transduction cascade. Disruption of ribbon synapse function in auditory hair cells, which detect acoustic vibrations, can cause deafness, demonstrating the central role of ribbons in auditory perception. More subtle observations of auditory ribbon synapses have revealed several puzzling properties that could influence functional encoding of auditory information. Specifically, measurements of neurotransmitter release from hair cells show simultaneous exocytosis of multiple vesicles, a phenomenon known as multivesicular release that represents a potential coding strategy for amplifying weak signals or for ensuring temporal precision of encoded auditory information. Additionally, in order to maintain a high rate of neurotransmitter release during sustained stimulation, the neurotransmitter vesicle pool must be continuously recycled, a process that involves endocytosis of previously fused vesicles. The mechanisms that regulate replenishment of the vesicle pool are poorly understood in hair cells, although observations from other neural systems provide clues about which intracellular signals might play regulatory roles in this process. Even less is known about the mechanisms that facilitate multivesicular release. These phenomena will be investigated using paired electrophysiological recordings from auditory hair cells and postsynaptic afferent fibers in the bullfrog (Rana catesbeiana) amphibian papilla. Experiments will be conducted using stimulation protocols and recording solutions specially designed to test the requirements for multivesicular release and the role of pH in controlling the rate of vesicle recycling. Computational tools will be developed for analyzing the instantaneous rate of exocytosis during complex evoked release events and for modeling presynaptic pH dynamics immediately following exocytosis. Results from these experiments have the potential to reveal molecular mechanisms and signaling strategies important not only to the process of auditory perception, but also to the general understanding of how sensory neurons encode and sustain information-rich signals describing a broad array of stimulus features.