1. Role of matrix metalloproteinase-9 in neurodevelopmental deficits and experience-dependent plasticity in Xenopus laevis .
- Author
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Gore SV, James EJ, Huang LC, Park JJ, Berghella A, Thompson AC, Cline HT, and Aizenman CD
- Subjects
- Animals, Humans, Matrix Metalloproteinase 9 genetics, Nervous System, Neurodevelopmental Disorders genetics, Neurogenesis genetics, Neurons, Seizures, Matrix Metalloproteinase 9 metabolism, Neurodevelopmental Disorders metabolism, Neurogenesis physiology, Xenopus laevis metabolism
- Abstract
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 may also lead to neurodevelopmental disorders (ND). Here, we test the hypothesis that chronically elevated MMP-9 activity during early neurodevelopment is responsible for neural circuit hyperconnectivity observed in Xenopus tadpoles after early exposure to valproic acid (VPA), a known teratogen associated with ND 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., Competing Interests: SG, EJ, LH, JP, AB, AT, HC, CA No competing interests declared, (© 2021, Gore et al.)
- Published
- 2021
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