Zhao Xuan

Biography:  Dr. Zhao Xuan, Assistant Professor of Neurobiolog, School of Biology and Ecology

COBRE Pilot Project:  In vivo interaction between the active and periactive zones in sustaining synaptic transmission

PROJECT SUMMARY: Neurons communicate via synapses. Loss of and dysfunction of synapses are associated with many neurodevelopmental and neurodegenerative diseases. Understanding the cellular and molecular mechanisms of synapse development and function is essential for revealing novel mechanisms underlying synaptic deficits in neurological diseases. At the presynaptic site, synaptic vesicles (containing neurotransmitters) are fused with the plasma membrane at the active zone, which is an electron-dense structure under the electron microscope. Adjacent to the active zone is a “hot spot” for synaptic vesicle endocytosis and endosomal sorting, the so-called periactive zone. Neurons can sustain high rates of synaptic transmission without exhausting their supply of synaptic vesicles, thanks to the local recycling of synaptic vesicles via endocytosis at the periactive zone. Genetic, morphological, and biochemical studies in the past two decades have facilitated a deep understanding of the identity, structure-function relationship, functions, and intermolecular interactions of the active zone proteins. However, comparably less is known regarding the adjacent periactive zone and its associated
cellular processes involved in synapse development and synaptic transmission. The periactive is a poorly defined sub-synaptic area that is composed of endocytic factors, accessory adaptor molecules, synaptic adhesion molecules, and regulators for actin assembly. Although individual periactive zone proteins were studied previously, a holistic view is needed to understand the interaction between the active and periactive zones in sustaining synaptic transmission. The objective of this application is to systematically catalog and stratify periactive zone proteins based on their function (e.g., essential, cooperative, or redundant) and interaction with the active zone proteins (e.g., synergistic, additive, or antagonistic) in sustaining synaptic transmission. We will take advantage of the powerful genetics and robust behavioral assays in C. elegans to investigate the interaction between the active and periactive zones in sustaining synaptic transmission using an aldicarb assay in C. elegans. Aldicarb assay provides an accurate comparative analysis of synaptic transmission in multiple worm strains in a short time. The completion of this study will provide data that enable me to apply for future NIH grants, such as R01 or R15, on investigating the interface between the active and periactive zones as a platform that allows crosstalk between the synaptic vesicle cycle and other cellular processes (e.g., autophagy) to achieve optimal synaptic performance. Periactive proteins (e.g., intersectin 1) are implicated in neurological diseases such as Down Syndrome, Alzheimer’s disease, and a severe, early-onset retinitis pigmentosa in humans. Understanding the functions of periactive zone proteins and how they coordinate with the active zone proteins to support synaptic transmission is an important first step toward discovering treatments for different neurological diseases.