Matrix metalloproteinases (MMPs) are a large family of mostly secreted, extracellularly acting proteolytic enzymes. In the brain, they have well-described roles in slowly emerging, but long-lasting pathophysiological processes of cell loss and synaptic dysfunction associated with acute injury, ischaemia, neurodegeneration and demyelination.
Remodelling of synapse structure and function also underlies normal cognitive processes, such as learning and memory. This Review focuses on recent studies that indicate that MMPs have important roles in driving such synapse plasticity under non-pathological conditions that are distinct from their roles in neuropathophysiology.
MMPs are secreted as inactive pro-enzymes (zymogens). Under basal conditions, a large pool of mostly pro-MMPs is situated perisynaptically, poised for activation by plasticity-inducing stimuli, such as long-term potentiation (LTP).
Upon induction of LTP, but not other forms of short- or long-lasting plasticity, pro-MMPs are rapidly (within ∼15 min) converted to proteolytically active MMPs through an NMDA receptor-dependent mechanism. Such proteolytically active MMPs then signal through β1-containing integrins to promote dendritic spine enlargement and synaptic potentiation concurrently.
Intercellular adhesion molecule 5, which binds to and activates integrins, may be a direct target of perisynaptic MMP proteolysis during LTP. LTP-associated MMP proteolysis is probably then terminated by an increase in the activity of endogenous inhibitors called tissue inhibitors of metalloproteinases.
When MMP activity is blocked pharmacologically or genetically, LTP, spine enlargement and behavioural measures of cognitive function are all impaired.
Several psychiatric and neurological disorders, including drug addiction, neuropathic pain syndromes and fragile X syndrome, are associated with abnormal or deficient synaptic plasticity. Recent studies indicate that aberrant MMP expression, localization and function may contribute to synaptic plasticity deficits associated with such disorders.
A key area for future research is to elucidate how MMP activity transitions from normal, adaptive roles in local synaptic remodelling to deleterious roles that have important pathophysiological cellular and synaptic consequences. This transition probably involves abnormal regulatory mechanisms, leading to excessive, prolonged and widespread MMP activity.
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.
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I thank. D. L Benson and V. Vialou for helpful comments on the manuscript, and V. Nagy, O. Bozdagi, P. Aujla, X. Wang and Q. Zhou for their scientific contributions to the personal work discussed in this Review. I am ever grateful to Ted Jones and Dave Colman — two prolific savants no longer with us — for their guidance and friendship over many years. My research was supported by the US National Institutes of Mental Health grant MH075783.
The author declares no competing financial interests.
A clan of metalloproteinases comprising matrix metalloproteinases (MMPs), a disintegrin and metalloproteinases (ADAMs) and ADAMs with thrombospondin repeats. It is so-named by an amalgam of two structural hallmarks of the active site region: a conserved methionine-containing turn downstream of — and positioned underneath to stabilize — a conserved zinc-binding motif (HExxHxxGxxH), in which the three histidine residues are zinc-binding ligands within the catalytic site.
- Dendritic spines
These are small actin-rich dendritic protrusions that harbour most of the excitatory glutamatergic synapses.
Proteolytic enzymes that are capable of cleaving gelatin (denatured collagen). In the matrix metalloproteinase (MMP) lexicon, the gelatinases are MMP2 (gelatinase A) and MMP9 (gelatinase B), as gelatin is a canonical substrate for these MMPs.
Heterodimers composed of an α- and a β-subunit. In mammals, there are 18 α- and eight β-subunits. They are canonical receptors of extracellular matrix and other proteins. In hippocampus, most integrin heterodimers contain the β1-subunit.
This is an actin-binding protein that is enriched in dendritic spines. Cofilin is a member of the ADF (actin-depolymerizing factor)–cofilin family and regulates the disassembly of filamentous actin. Cofilin is negatively regulated by phosphorylation at a single site (Ser3).
Soluble NSF (N-ethylmaleimide-sensitive factor) attachment protein (SNAP) receptor. A family of proteins comprising vesicular (v)-SNAREs and target (t)-SNAREs that mediate intracellular membrane fusion.
- Miniature excitatory postsynaptic potentials
(mEPSCs). These are the postsynaptic responses to a quantum of excitatory neurotransmitter (usually glutamate).
- Conditioned place preference
(CPP). A behavioural task that is used to evaluate an animal's preference for stimuli or an environment associated with positive or negative reward.
Secondary substrate-binding sites on an enzyme that are distinct from the catalytic active site. Exosites are often important for positioning substrates for full proteolytic cleavage.
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Huntley, G. Synaptic circuit remodelling by matrix metalloproteinases in health and disease. Nat Rev Neurosci 13, 743–757 (2012). https://doi.org/10.1038/nrn3320
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