Elevated matrix metalloproteinase-9 and degradation of perineuronal nets in cerebrocortical multiple sclerosis plaques.
ABSTRACT Matrix metalloproteinases (MMPs) degrade extracellular matrix; MMP activity, particularly of MMP-9, is elevated in the white matter in multiple sclerosis (MS) patients. The cerebral cortical extracellular matrix includes perineuronal nets (PNs) that surround parvalbumin-positive neurons (PV-positive neurons) and are important for their function. We measured active and total MMP-9 levels in postmortem homogenates of demyelinated and nondemyelinated cerebral cortical regions from 9MS and 7 control cases and assessed Wisteria floribunda agglutin (WFA)-positive PNs in paraffin sections from 15 MS and 6 controls and PV-positive neurons in sections from 26 MS and 6 controls. Active MMP-9 levels were higher in demyelinated than in nondemyelinated or control cortex (p < 0.05). The area fraction positive for WFA was lower in demyelinated than nondemyelinated MS or control cortex; the latter difference was significant (p < 0.05). Most PV-positive neurons in demyelinated but not intact cortex lackeda PN, and some showed perikaryal phosphorylated neurofilament protein accumulation. Loss of WFA-labeled PNs was not associated with reduced PV-positive neurons numbers. Thus, elevated MMP-9 in cortical plaques is associated with loss of PNs; PV-positive neurons are preserved but show abnormal neurofilament accumulations. Matrix metalloproteinase-mediated degradation of PNs in cortical plaques may, therefore, contribute to neuronal dysfunction and degeneration in MS patients.
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ABSTRACT: Perineuronal nets (PNNs) were shown to be markedly altered in subjects with schizophrenia. In particular, decreases of PNNs have been detected in the amygdala, entorhinal cortex and prefrontal cortex. The formation of these specialized extracellular matrix (ECM) aggregates during postnatal development, their functions, and association with distinct populations of GABAergic interneurons, bear great relevance to the pathophysiology of schizophrenia. PNNs gradually mature in an experience-dependent manner during late stages of postnatal development, overlapping with the prodromal period/age of onset of schizophrenia. Throughout adulthood, PNNs regulate neuronal properties, including synaptic remodeling, cell membrane compartmentalization and subsequent regulation of glutamate receptors and calcium channels, and susceptibility to oxidative stress. With the present paper, we discuss evidence for PNN abnormalities in schizophrenia, the potential functional impact of such abnormalities on inhibitory circuits and, in turn, cognitive and emotion processing. We integrate these considerations with results from recent genetic studies showing genetic susceptibility for schizophrenia associated with genes encoding for PNN components, matrix-regulating molecules and immune system factors. Notably, the composition of PNNs is regulated dynamically in response to factors such as fear, reward, stress, and immune response. This regulation occurs through families of matrix metalloproteinases that cleave ECM components, altering their functions and affecting plasticity. Several metalloproteinases have been proposed as vulnerability factors for schizophrenia. We speculate that the physiological process of PNN remodeling may be disrupted in schizophrenia as a result of interactions between matrix remodeling processes and immune system dysregulation. In turn, these mechanisms may contribute to the dysfunction of GABAergic neurons.Schizophrenia Research 01/2015; 134. · 4.43 Impact Factor
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ABSTRACT: Schizophrenia is a complex brain disorder associated with deficits in synaptic connectivity. The insidious onset of this illness during late adolescence and early adulthood has been reported to be dependent on several key processes of brain development including synaptic refinement, myelination and the physiological maturation of inhibitory neural networks. Interestingly, these events coincide with the appearance of perineuronal nets (PNNs), reticular structures comprised of components of the extracellular matrix that coat a variety of cells in the mammalian brain. Until recently, the functions of the PNN had remained enigmatic, but are now considered to be important in development of the central nervous system, neuronal protection and synaptic plasticity, all elements which have been associated with schizophrenia. Here, we review the emerging evidence linking PNNs to schizophrenia. Future studies aimed at further elucidating the functions of PNNs will provide new insights into the pathophysiology of schizophrenia leading to the identification of novel therapeutic targets with the potential to restore normal synaptic integrity in the brain of patients afflicted by this illness.Neuroscience & Biobehavioral Reviews 09/2014; · 10.28 Impact Factor
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ABSTRACT: Matrix metalloproteinases (MMPs) are a family of extracellular proteases associated with extracellular matrix remodeling. They are involved in many physiological and reparative processes. MMPs can break down all extracellular constituents; therefore, their expression is very tightly regulated and their abnormal activity or over production has been linked to many diseases including multiple sclerosis (MS) which is a leading cause of non-traumatic disability in young adults in North America. Recently many studies, both in animals and humans, have been conducted to better elucidate the underlying causes, mechanisms and pathophysiology of MS. In this review, we discuss the potential role of pathological upregulation of MMPs in MS and future challenges which if properly addressed might help in development of potential cure for this disease.Acta neurologica Belgica. 09/2013; 113(4).