Neuronal and glial mechanisms regulating Pair1 local pruning

Oregon Health & Science University, Portland OR

Investigators

Abstract

Project Summary Developing brains over-wire and create excess synaptic connections. The nervous system then undergoes neuronal remodeling by implementing structural changes through pruning of superfluous neurons and synapses. Neurons and glia communicate intensively during the remodeling process, but the mechanistic basis of neuronal or glial signaling remain understudied and poorly defined. Disrupted remodeling has implications on behavior and circuitry in neurodevelopmental disorders, like autism spectrum disorder (ASD), and even neurodegenerative diseases like Alzheimer’s, highlighting the importance of defining this process. There are strong correlations between broad changes in neural circuit connectivity and behavioral changes in ASD animal models and patients. This has led to the proposal that broad changes in neuronal remodeling during development cause behavioral changes, but this idea has not been tested directly and the link between structural changes in circuits (e.g. local pruning of neurites) and behavior remains unclear. Drosophila Pair1 neurons, a circuit where 6 neurons drive reversal behavior in the larva and adult, provide an excellent model to study both neuronal and glial molecular mechanisms of remodeling, and investigate how perturbation of remodeling affects behavior and circuit morphology. In preliminary work I have defined the morphology of their local pruning and identified caspase signaling as a key neuron-intrinsic pathway that drives pruning. In Aim 1, I will investigate intrinsic mechanisms for Pair1 local pruning by exploring known caspase cascades in the context of Pair1 pruning using loss-of-function studies and caspase indicators with live ex-vivo imaging. In Aim 2, I will determine if astrocytes are responsible for activating Pair1 remodeling and clearing pruned debris, and conduct a targeted genetic screen for glial molecules required for pruning of Pair1 neurons. In Aim 3, I will block intrinsic remodeling cues in Pair1 neurons to ask if altering Pair1 local pruning affects assembly of adult circuitry and behavior. Together, these aims will contribute new fundamental knowledge to the remodeling field, which ultimately will help us understand how brain circuits are optimized and how changes in remodeling might affect behavioral phenotypes in neurological disorders and disease. The training potential for me is very high in this project, and my proposed research will help me achieve both my research and professional training goals. I will deeply expand my knowledge in both the glial and neurodevelopmental biology fields, while also gaining many new technical skills in the laboratory. Outside of the laboratory, I will consistently seek career development opportunities to advance my communication skills, leadership, and equity and inclusion education and impact. I am strongly supported in my training goals from my sponsor Dr. Marc Freeman, the Vollum Institute, and OHSU and know I will succeed with the support of this award.