Time dependent integration of matrix metalloproteinases and their targeted substrates directs axonal sprouting and synaptogenesis following central nervous system injury

Abstract

Over the past two decades, many investigators have reported how extracellular matrix molecules act to regulate neuroplasticity. The majority of these studies involve proteins which are targets of matrix metalloproteinases. Importantly, these enzyme/substrate interactions can regulate degenerative and regenerative phases of synaptic plasticity, directing axonal and dendritic reorganization after brain insult. The present review first summarizes literature support for the prominent role of matrix metalloproteinases during neuroregeneration, followed by a discussion of data contrasting adaptive and maladaptive neuroplasticity that reveals time-dependent metalloproteinase/substrate regulation of postinjury synaptic recovery. The potential for these enzymes to serve as therapeutic targets for enhanced neuroplasticity after brain injury is illustrated with experiments demonstrating that metalloproteinase inhibitors can alter adaptive and maladaptive outcome. Finally, the complexity of metalloproteinase role in reactive synaptogenesis is revealed in new studies showing how these enzymes interact with immune molecules to mediate cellular response in the local regenerative environment, and are regulated by novel binding partners in the brain extracellular matrix. Together, these different examples show the complexity with which metalloproteinases are integrated into the process of neuroregeneration, and point to a promising new angle for future studies exploring how to facilitate brain plasticity.

Matrix metalloproteinases as promising regulators of axonal regrowth in the injured adult zebrafish retinotectal system

“…Consequently, Mmp‐9 could be involved in synaptic plasticity or regrowth in the regenerating zebrafish retina, a process not yet examined. This finding is in accordance with the wide range of results that imply MMPs, and MMP‐9 in particular, as primordial players in hippocampal plasticity and reactive synaptogenesis after injury in the adult mammalian brain (Ethell and Ethell, ; Verslegers et al, ; Phillips et al, ; Tsilibary et al, ).…”

Motor System Reorganization After Stroke: Stimulating and Training Toward Perfection

“…Briefly, degeneration elevates molecules that promote cell survival and proliferation and the structural remodeling of dendrites, axons, and synapses (157,198). Growth inhibitory molecules that normally limit axonal plasticity in the adult brain are reduced (33, 130), and surviving neurons sprout new axon collaterals to reinnervate neurons in the penumbra and other denervated regions (17,155).…”

“…Axonal sprouting and synaptogenesis are coordinated with dendritic remodeling in postsynaptic (2, 41, 187) and presynaptic (7, 152) neurons. The neuronal growth responses are intercoordinated with glial, vascular (10, 80), and extracellular matrix remodeling (157,171). The whole process yields a system with new connectivity patterns, sometimes with much altered excitatory and inhibitory activity patterns (34,96,193).…”

MMP‐9 in translation: from molecule to brain physiology, pathology, and therapy

“…Treatment with an MMP inhibitor reduced BBB disruption and brain water accumulation. In aggregate, MMP-9 appears to contribute to both neuronal cell loss following TBI and the facilitation of regenerative processes (Jourquin et al 2003;Reeves et al 2003;Chan et al 2014;Phillips et al 2014).…”