Main projects in the lab: 1) Determine how a sensory stimulus are encoded within an intact sensory system It is extremely challenging in mammalian systems to study complex spatio-temporal signals within a cell or among cells to understand how populations of hair cells work in concert to encode sensory stimuli in vivo. We are using neuromasts of the zebrafish lateral line to model organ to study how of hair cells work in concert to encode sensory stimuli in vivo. For example, within a neuromast organ, how does a sensory stimulus activate all hair cells in the organ, and how do all the cells and synapses coordinate to convert that information into a meaningful signal that is sent to the brain. Our studies use transgenic lines expressing genetically encoded indicators and high-speed confocal imaging to measure hair cell calcium signals, vesicle release and postsynaptic responses with precise temporal and spatial resolution in all cells and synapses within a neuromast organ. This information is providing new insight on how hair cells cooperate to encode sensory stimuli. 2) Determine how synaptic calcium modulate hair-cell synapse assembly Our current understanding of hair-cell synapse formation has been largely obtained by studies that examined morphological or functional changes at single time points during development. Although this work has been informative, development is dynamic, and local synaptic activity is thought to play an active role shaping synapse assembly. We have used the zebrafish model to examine the relationship between synaptic activity and ribbon assembly in vivo. Our previous findings indicated that a pharmacological activation or inhibition of synaptic calcium could push developing synapses towards assembly or disassembly, respectively, on relatively short timescales. Currently we have examined how presynaptic calcium levels are controlled at developing ribbons. Our work indicate that hair-cell synapse assembly is controlled by calcium stores. This work provides mechanistic insight into how activity in hair cells regulates synapse assembly during development and knowledge required to reform synapses under pathological conditions. 3) Understand the molecular components that are vital for hair-cell synapses This work seeks to identify novel components required at the hair-cell synapse. We are using zebrafish as a high throughput platform to examine whole gene families to identify novel molecules required for ribbon synapse function, development and regeneration. We are currently characterizing several of these mutants for phenotypes using functional imaging techniques. Uncovering the machinery that enables hair-cell synapses to function and form will enable us to understand fundamental biological questions including how this specialized synapse works to encode auditory and vestibular information. In addition, this work could have clinical applications, including uncovering new human deafness loci associated with syndromic or nonsyndromic hearing loss.
