I began studying neuronal physiology as an undergraduate at Stanford with Dr. Richard Aldrich and continued in the lab of Dr. Wade Regehr at Harvard Medical School. For my thesis, I studied synaptic transmission in acute brain slices from rat cerebellar cortex, focusing on two major projects: presynaptic modulation by neurotransmitter-activated G protein-coupled receptors (GPCRs), and calcium-dependence of presynaptic short-term plasticity. I combined photoactivation with calcium imaging and electrophysiological recordings from Purkinje cells to describe the mechanism of heterosynaptic depression at the parallel fiber to Purkinje cell synapse mediated by extrasynaptic GABA signaling. In addition, I characterized a novel form of short-term plasticity at the climbing fiber to Purkinje cell synapse based on a calcium-driven acceleration of recovery from presynaptic depression.
I took a more molecular approach for my postdoctoral research with Dr. Joshua Kaplan at MGH by using C. elegans as a model system for understanding synaptic function. I developed a variety of quantitative optical approaches to characterize synaptic function in C. elegans. Fluorescently-tagged synaptic proteins were imaged in the nerve cords of intact animals. I created automated analysis software to quantify the intensity and spatial distribution of fluorescence. This was used to characterize the trafficking and localization defects of mutants in the postsynaptic glutamate receptor regulatory pathway, and to monitor presynaptic parameters in synaptic release mutants. I also used a pH-sensitive GFP to measure the surface and internal pools of the vesicle protein, Synaptobrevin. I developed quantitative assays to determine the specific aspects of locomotion behaviors that are altered when synaptic activity is modulated. Combining these assays with a pharmacological treatment that enhances ACh spillover, I identified three motor neuron GPCRs mediating homosynaptic and heterosynaptic depression. In RNAi screens, I identified four neurotransmitter-activated GPCRs that were negatively coupled to ACh release: gar-2 mACh receptor, gbb-1/2 GABAB receptor dimer, and mgl-1 mGlu receptor.