Journal Article

Synaptic circuit remodelling by matrix metalloproteinases in health and disease

Huntley, George W.

2012

Overview

Key Points 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. Aberrant matrix metalloproteinase (MMP) activity is a well-known contributor to synaptic dysfunction and neuronal loss in CNS injury and disease. In this Review, George W. Huntley discusses how MMPs also make an important contribution to synaptic functional and structural remodelling under nonpathophysiological conditions. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/378/2591 / 631/45/468 / 631/45/474 / 692/699/375 / Animal Genetics and Genomics / Animals / Behavioral Sciences / Biological activity / Biological and medical sciences / Biological Techniques / Biomedical and Life Sciences / Biomedicine / Cell adhesion & migration / Central nervous system / Central neurotransmission. Neuromudulation. Pathways and receptors / Cognition & reasoning / Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases / Disease / Enzyme Activation - physiology / Fundamental and applied biological sciences. Psychology / Growth factors / Health aspects / Health Status / Humans / Ligands / Matrix Metalloproteinases - physiology / Medical sciences / Metalloproteins / Nerve Net - enzymology / Nerve Net - physiopathology / Nervous System Diseases - enzymology / Nervous System Diseases - physiopathology / Neural circuitry / Neural transmission / Neurobiology / Neurology / Neuronal Plasticity - physiology / Neurosciences / Peptides / Physiological aspects / Proteases / Proteins / review-article / Synapses - enzymology / Vertebrates: nervous system and sense organs