CAREER: Understanding the Dynamic Regulation of Extracellular Matrix in Controlling Synaptic Homeostasis

The brain’s ability to process information relies on synapses, the vital connections between nerve cells. These connections are adaptable, supporting learning and memory, while also remaining stable to ensure proper brain function. The extracellular matrix, a network of molecules surrounding synapses, plays a critical role in maintaining this balance. This investigation explores how changes in this matrix affect synapse stability and, consequently, the brain’s ability to function effectively. This work is vital because disruptions in synapse stability are linked to neurological disorders such as epilepsy, autism, and Alzheimer’s disease. By uncovering the mechanisms that preserve brain connectivity, we aim to inspire new strategies for addressing these challenging conditions. This project goes beyond scientific discovery to inspire and empower the next generation of scientists, contributing to our nation’s leadership in science and technology. Through engaging educational initiatives, we provide hands-on STEM experiences, focusing on providing opportunities for all. A highlight of our outreach includes LEGO-based microscopes, which combine creativity and science to make microscopy accessible and fun for all ages. Additionally, we integrate art and science, encouraging students to explore scientific concepts through creative expression. Our mission is to equip students with the tools and inspiration to excel in STEM and drive societal progress. Synaptic connections between neurons are essential for brain function, balancing adaptability for information processing with stability to maintain circuit integrity. Homeostatic plasticity ensures neural circuits remain adaptive within physiological limits, yet its molecular pathways are poorly understood. Disruptions in homeostatic signaling contribute to excitation-inhibition imbalances implicated in neurological disorders such as epilepsy, Autism Spectrum Disorder, and Alzheimer’s disease. The extracellular matrix (ECM), which provides structural support and serves as a reservoir for signaling molecules, plays a critical but understudied role in regulating synaptic function. This research focuses on how the ECM maintains synaptic stability through dynamic regulation by matrix metalloproteinases. Using Drosophila melanogaster as a model, we identified Drosophila Multiplexin (Dmp), a homolog of mammalian Collagen XVIII, as a key regulator of homeostatic plasticity. Proteolytic cleavage of Dmp releases Endostatin, a signaling factor essential for synaptic stability. This project will investigate how matrix metalloproteinases regulate ECM dynamics during different phases of synaptic homeostasis and elucidate the mechanisms by which ECM signaling modulates presynaptic neurotransmitter release. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.