Role of matrix metalloproteinase-9 in neurodevelopmental deficits and experience-dependent plasticity in Xenopus laevis.

Sayali V Gore,Eric J James,Hollis T Cline,Andrea Berghella,Carlos D Aizenman,Adrian C Thompson,Lin-Chien Huang,Jenn J Park

doi:10.7554/elife.62147

Sayali V Gore, Eric J James + Show 6 more

Open Access

https://doi.org/10.7554/elife.62147

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Journal: eLife	Publication Date: Jul 20, 2021
Citations: 7	License type: CC BY 4.0

Affiliation: Brown University, Scripps Research Institute

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.

Highlights

Autism spectrum disorder (ASD) encompasses a highly heterogeneous set of neurodevelopmental conditions characterized by a complex behavioral phenotype and deficits in both social and cognitive functions
We first tested whether overexpression of Matrix metalloproteinase-9 (MMP-9) mimics the VPA127 induced effects on synaptic connectivity and excitability in the developing tectum
The change in dendritic growth rate was significantly decreased in the SB-3CT reared tadpoles in comparison to the matched control animals [Change in growth rate (%): Control, 136.61 ± 12.29, n = 9; SB-3CT, 91.27 ± 6.42, n = 9; p = 0.009] (Fig. 5D, E). These results suggest that enhanced visual stimulation increased MMP-9 levels, and that this increase is necessary for proper activity-driven dendritic arborization

Summary

Introduction

Autism spectrum disorder (ASD) encompasses a highly heterogeneous set of neurodevelopmental conditions characterized by a complex behavioral phenotype and deficits in both social and cognitive functions. In utero exposure to VPA results in autistic-like behaviors in offspring; namely decreased socialization, increased repetitive behaviors, and hypersensitivity to sensory stimuli (Kataoka et al, 2013; Kim et al, 2011; Mehta et al, 2011; Moldrich et al, 2013) These behavioral deficits are accompanied by corresponding deficits in brain physiology, including increased local recurrent connectivity, synaptic activity, and decreased intrinsic neuronal excitability (Markram and Markram, 2010). Xenopus tadpoles when exposed to VPA have abnormal sensory-motor and schooling behavior which is accompanied by hyper-connected neural networks in the optic tectum, increased excitatory and inhibitory synaptic drive, elevated levels of spontaneous synaptic activity and decreased neuronal intrinsic excitability(James et al, 2015). MMP-9 is thought to play a role in adult neurogenesis and synaptic plasticity in the adult brain, and has been implicated in neural circuit formation (Fujioka et al, 2012; Peixoto et al, 2012; Pielecka-Fortuna et al, 2015; Wang et al, 2008)

Results

Discussion

Materials and Methods