Role of matrix metalloproteinase-9 in neurodevelopmental disorders and experience-dependent plasticity in Xenopus tadpoles

Abstract

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. Summary:Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social and cognitive functions. Prenatal exposure to valproic acid (VPA) results in ASD in humans and in neurodevelopmental abnormalities in other animal models. Similarly, exposure to VPA during a critical developmental period in Xenopus tadpoles causes behavioral and electrophysiological abnormalities consistent with hyperconnected neural networks. VPA exposure results in upregulation of matrix metalloproteinase-9 (MMP-9) levels in tadpole brains,

BDNF signaling in correlation-dependent structural plasticity in the developing visual system

“…There is evidence to suggest that MMP-9 is involved in the processing of proBDNF to mBDNF leading to stabilization of a robustly firing motor axon in the NMJ, or in strengthening of co-active synapses in the CNS (Je et al, 2012; Niculescu et al, 2018). In the Xenopus optic tectum, MMP-9 is necessary for the visual experience driven increase in tectal neuron dendritic growth (Gore et al ., 2021). Results from computational modeling suggest that the ratio of proBDNF/mBDNF, regulated by local action of MMP-9, combined with a precisely-timed rise in postsynaptic calcium may be crucial to switch plasticity from depression to potentiation, presumably due to preferential activation of p75 NTR and TrkB, respectively (Kirchner and Gjorgjieva, 2021).…”

“…In the Xenopus optic tectum, MMP-9 is necessary for the visual experience driven increase in tectal neuron dendritic growth (Gore et al, 2021). Results from computational modeling suggest that the ratio of proBDNF/mBDNF, regulated by local action of MMP-9, combined with a precisely-timed rise in postsynaptic calcium may be crucial to switch plasticity from depression to potentiation, presumably due to preferential activation of p75 NTR and TrkB, respectively (Kirchner and Gjorgjieva, 2021).…”