A delicate balance: role of MMP-9 in brain development and pathophysiology of neurodevelopmental disorders

Abstract

The extracellular matrix (ECM) is a critical regulator of neural network development and plasticity. As neuronal circuits develop, the ECM stabilizes synaptic contacts, while its cleavage has both permissive and active roles in the regulation of plasticity. Matrix metalloproteinase 9 (MMP-9) is a member of a large family of zinc-dependent endopeptidases that can cleave ECM and several cell surface receptors allowing for synaptic and circuit level reorganization. It is becoming increasingly clear that the regulated activity of MMP-9 is critical for central nervous system (CNS) development. In particular, MMP-9 has a role in the development of sensory circuits during early postnatal periods, called ‘critical periods.’ MMP-9 can regulate sensory-mediated, local circuit reorganization through its ability to control synaptogenesis, axonal pathfinding and myelination. Although activity-dependent activation of MMP-9 at specific synapses plays an important role in multiple plasticity mechanisms throughout the CNS, misregulated activation of the enzyme is implicated in a number of neurodegenerative disorders, including traumatic brain injury, multiple sclerosis, and Alzheimer’s disease. Growing evidence also suggests a role for MMP-9 in the pathophysiology of neurodevelopmental disorders including Fragile X Syndrome. This review outlines the various actions of MMP-9 during postnatal brain development, critical for future studies exploring novel therapeutic strategies for neurodevelopmental disorders.

Two classes of matrix metalloproteinases reciprocally regulate synaptogenesis

“…By contrast, the Drosophila genome encodes just one secreted Mmp (Mmp1), one membrane Mmp (GPI-anchored Mmp2) and one secreted Timp. In lieu of mammalian studies, which show that extracellular proteases play central roles determining synapse structure, function and number (reviewed in Reinhard et al, 2015;Shinoe and Goda, 2015;Wójtowicz et al, 2015), we took advantage of the reductionist Drosophila model to genetically dissect the complete, integrated mechanism of the matrix metalloproteome in synaptic development.…”

Polymorphisms in the matrix metalloproteinase-9 promoters and susceptibility to glial tumors in turkey

“…The MMP-9 gene has functions in embryonic development, reproduction, tissue remodeling, carcinogenesis, and metastasis (12,27,35). Moreover, to date, many MMP-9 related polymorphism studies have been performed to clarify its role in different steps of carcinogenesis in various cancer types including colorectal, gastric, head and neck carcinomas, renal cell cancer, endometrium carcinoma, prostate cancer, oral cavity carcinoma, breast cancer, malignant melanoma, nasopharynx cancer, and esophagus cancer.…”

Secreted tissue inhibitor of matrix metalloproteinase restricts trans-synaptic signaling to coordinate synaptogenesis

“…These studies provide an avenue for possible therapeutic treatments in a range of neurological disease states with elevated Mmp activity (Hadler-Olsen et al, 2011;Reinhard et al, 2015). In particular, Mmp hyperactivity has been causally implicated in FXS and related ASD conditions (Abdallah and Michel, 2013;Dziembowska et al, 2013;Sidhu et al, 2014;Siller and Broadie, 2011).…”

“…Improper Mmp expression and activity is implicated in a range of neurological disorders, including schizophrenia (Lepeta and Kaczmarek, 2015), addiction (Liu et al, 2010), epilepsy (Pollock et al, 2014) and autism spectrum disorder (ASD) (Abdallah and Michel, 2013). As the most common heritable ASD and intellectual disability, Fragile X syndrome (FXS) underscores the importance of preserving Mmp balance to control proper synaptic structure and function (Reinhard et al, 2015;Siller and Broadie, 2011). Importantly, the Mmp inhibitor minocycline alleviates synaptic and behavioral phenotypes in FXS disease models (Bilousova et al, 2009;Broadie, 2011, 2012), and has shown promise in clinical trials for human patients , showing that elevated Mmp activity is causally linked to FXS neuropathology (Doll and Broadie, 2014).…”