Synaptic circuit remodelling by matrix metalloproteinases in health and disease

Abstract

Matrix metalloproteinases (MMPs) are extracellularly acting enzymes that have long been known to have deleterious roles in brain injury and disease. In particular, widespread and protracted MMP activity can contribute to neuronal loss and synaptic dysfunction. However, recent studies show that rapid and focal MMP-mediated proteolysis proactively drives synaptic structural and functional remodelling that is crucial for ongoing cognitive processes. Deficits in synaptic remodelling are associated with psychiatric and neurological disorders, and aberrant MMP expression or function may contribute to the molecular mechanisms underlying these deficits. This Review explores the paradigm shift in our understanding of the contribution of MMPs to normal and abnormal synaptic plasticity and function.

FIGURE 1. MMP9 localization and activity in hippocampus before and after LTP

a Under basal conditions in adult hippocampal area CA1, numerous matrix metalloproteinase 9 (MMP9) immunofluorescent puncta are present within the synaptic neuropil of stratum radiatum (a). Many such puncta codistribute with labelling for other synaptic molecular markers, for example, vGluts (vesicular glutamate transporters), which is a marker of excitatory presynaptic terminals (insets), indicating perisynaptic localization. Much of this perisynaptic immunoreactivity is probably the inactive pro-form, as there are few gelatinolytic puncta (hotspots of proteolytic activity) present under control conditions (b). Following induction of long-term potentiation (LTP) (c, image taken 75 minutes after LTP induction), there is a significant increase in numbers of gelatinolytic puncta. In the absence of LTP because of prior administration of the NMDA receptor (NMDAR) antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), there is no increase in proteolysis (d), thus, MMP activation is related specifically to LTP and is not a non-specific effect of trains of electrical stimuli. At higher-power, many of the gelatinolytic puncta (e, gel’lysis) codistribute with MMP9 immunoreactivity (f,g, arrows), which consistent with the activation of MMP9 with LTP induction. Images B–G are adapted from REF . Bars represent 50 μm (A); 10 μm (B–D); 3 μm (E–G).

FIGURE 2. A model of MMP9 activity in driving synaptic structural and functional remodelling

Under basal conditions, mostly pro-forms of matrix metalloproteinase 9 (MMP9) are localized perisynaptically in CA1. Upon LTP induction, postsynaptic NMDA-type glutamate receptor (NMDAR) activity triggers rapid and local nitric oxide (NO) release into the perisynaptic microenvironment, which in turn converts pro-MMP9 to proteolytically active MMP9. Once proteolytically active, MMP9 cleaves perisynaptic intracellular adhesion molecule 5 (ICAM5). The ICAM5 ectodomain then binds to and activates postsynaptic β1-containing integrins, which in turn triggers actin polymerization in part through phosphorylation of cofilin. Actin polymerization is the basis for an integrin-mediated consolidation process of spine structural enlargement as well as AMPA receptor (AMPAR) trafficking into the synaptic membrane. New pro-MMP9 synthesis and release by pre- and postsynaptic neurons and/or perisynaptic astrocytes replenishes the extracellular pool of pro-MMP9. In time, tissue inhibitors of metalloproteinases (TIMPs) are released to terminate MMP9 activity.

FIGURE 3. Transition of MMP activity to pathophysiological processes

a | Both experimentally induced and behaviorally induced forms of synaptic plasticity affect a minority of synapses that are widely distributed. Thus, during long-term potentiation LTP, matrix metalloproteinases (MMPs) are activated locally at a minority of synapses distributed widely throughout the neuropil. Within ~15 min, active MMP9 coordinately drives dendritic spine enlargement (arrow) and potentiation as part of an integrin-dependent consolidation process. After 1–2 hours, MMP activity is terminated, most likely by increased tissue inhibitor of metalloproteinase (TIMP) activity. b | By contrast, under pathophysiological conditions, ischaemic or inflammatory disruption of the blood–brain barrier (BBB) results initially from aberrant expression of a number of MMPs within the neurovascular unit. Such MMP-mediated activity leads to subsequent invasion into the brain parenchyma of inflammatory and other cell types, which in turn triggers further aberrant MMP expression and secretion by astrocytes, neurons and microglia. Under these conditions, MMPs are activated by each other and by free radicals such as nitric oxide. Such excessive and active MMPs then infiltrate networks of neurons and their synapses. Broad and sustained MMP exposure at all or most synapses of a network lead to conversion of dendritic spines to immature-like filopodia (inset), followed by synapse breakdown and, eventually, neuronal apoptosis.