Carlos Aizenman, PhD
Professor
Department of Neuroscience
Brown University
(April 20, 2021)
Role of Matrix Metalloproteases in Neurodevelopmental Disorders
Normal brain development is a carefully regulated process. Alterations to any part of the process can lead to potentially severe dysfunction. Certain medications, for example, are discouraged during pregnancy, as they can disrupt the balance needed for optimal development. Dr. Aizenman discussed his work on valproic acid (an anti-seizure medication) and how it can disrupt neural development, leading to autism-like traits. Using tadpoles as a model organism, he has shown that autism traits are seen when an enzyme normally present in the brain is overproduced. Importantly, blocking this enzyme reverses the effects of valproic acid on both brain physiology and behavior.
Matrix metalloproteinase-9 (MMP-9) is a secreted endopeptidase targeting extracellular matrix proteins, creating permissive environments for neuronal development and plasticity. Developmental dysregulation of MMP-9 is also associated with neurodevelopmental disorders (ND). In this presentation, we examine the hypothesis that chronically elevated MMP-9 activity during early neurodevelopment is responsible for neural circuit hyperconnectivity observed after early exposure to valproic acid (VPA), a known teratogen associated with autism spectrum disorder in humans. In Xenopus tadpoles, VPA exposure results in excess local synaptic connectivity, disrupted social behavior and increased seizure susceptibility. We found that overexpressing MMP-9 in the brain copies effects of VPA on synaptic connectivity, and blocking MMP-9 activity pharmacologically or genetically reverses effects of VPA on physiology and behavior. We further show that during normal neurodevelopment MMP-9 levels are tightly regulated by neuronal activity and required for structural plasticity. These studies show a critical role for MMP-9 in both normal and abnormal development.