The role of matrix metalloproteinase-9 (MMP-9) in neurodevelopmental deficits and experience-dependent structural plasticity in Xenopus laevis tadpoles

Matrix metalloproteinase-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 chronica...

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Bibliographic Details
Published inbioRxiv
Main Authors Gore, Sayali, James, Eric J, Lin-Chien, Huang, Park, Jenn J, Berghella, Andrea, Cline, Hollis T, Aizenman, Carlos D
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 31.05.2020
Subjects
Developmental plasticity
Endopeptidase
Extracellular matrix
Gelatinase B
Juveniles
Matrix metalloproteinase
Metalloproteinase
Neural networks
Neurodevelopmental disorders
Seizures
Social behavior
Valproic acid
Xenopus
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Summary:Matrix metalloproteinase-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 either 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 Interest Statement The authors have declared no competing interest.
DOI:10.1101/2020.05.29.123661