Table 2 |.

Extracellular matrix remodelling in epileptogenesis

ECM component and/or remodelling molecules	Source	Functions	Pathology and/or epileptogenic effects	Refs
CSPG and/or CS-GAGs	Neurons, astrocytes and radial glia	Ionic homeostasis Synaptic stabilization and plasticity Neuroprotection Regulate localization of receptors on membrane	Altered after CNS injury and epilepsy Reactive glia-secreted CSPGs form glial scar and inhibit axon regeneration Epileptiform activity, altered chloride homeostasis and decreased inhibition on CSPGs and/or PNN disruption	110,118,133,136
HSPGs and/or glypicans	Astrocytes, neurons and endothelial cells	Synaptogenesis and synaptic maturation	Downregulated in epilepsy models Unaltered in individuals with TLE Upregulated after CNS injury	136–138
Tenascin C	Astrocytes, neurons, radial glial and epithelial cells	Synaptic plasticity Regulates astrocyte progenitor proliferation and astroglial maturation	Upregulated in seizure models associated with gliosis and axonal sprouting Excessive release after injury and/or seizure Impaired LTP, astrogliosis and low density of PV+ interneurons with tenascin C deficiency	12,103,139,140
Tenascin R	Neurons and oligodendrocytes	Synaptic plasticity Functional modulation of sodium channels	Upregulated after injury, lesion and epilepsy Abnormal PNN formation, impaired LTP, gliosis and decreased excitatory synapses and axonal conduction velocity on tenascin R deficiency	12,103,140–142
HA	Neurons and astrocytes	Regulation of extracellular space Cell migration and signalling	Upregulated in individuals with TLE Epileptiform activity and impaired LTP with HA depletion Spontaneous seizures with HA deficiency	103,108,109,136
MMPs	Astrocytes, endothelial cells, neurons, microglia and oligodendrocytes	ECM remodelling and cell migration Synaptic morphology regulation	Upregulated in CNS injury and seizure Causes aberrant synaptogenesis associated with epileptic seizures Decreased seizure sensitivity in MMP9-knockout mice Increased seizure sensitivity in MMP-overexpressing mice	12,105,106,143,144
ADAMTs	Neurons, astrocytes, microglia, monocytes and macrophages	Proteoglycanase activity Regulation of neural plasticity and regeneration Inflammatory and antiangiogenic actions	Upregulated in reactive astrocytes after seizure and CNS injury Proteolytic cleavage of reelin Deficiency causes reduction in synaptic proteins and an increase in neurocan	103,145–147
tPA	Neurons and microglia	Serine proteases activating plasmin and MMPs Regulation of neuronal development and survival and synaptic function Modulation of synaptic plasticity	Upregulation in epilepsy Mossy fibre sprouting during epileptogenesis Reduced synaptic plasticity and delayed seizure progression in knockout mice	103,146,148
TSPs	Astrocytes and macrophages	Excitatory synaptogenesis Modulation of cellular signalling, cell adhesion and migration	Upregulated in reactive astrocytes after injury Astrogliosis and decreased number of excitatory synapses with TSP deficiency	12,140
Reelin	Cajal-Retzius cells and interneurons	Synaptogenesis and cortical lamination Integration of DGCs	Impaired formation of DGCs in individuals with TLE and rodent models of epilepsy with reelin loss Autosomal dominant TLE in heterozygous mutations DGC dispersion, neuronal heterotopia and enhanced seizure susceptibility in knockout mice	103,149
Hevin	Vasculature cells, astrocytes, radial glia and neurons	Excitatory synaptogenesis Cortical lamination Synaptic plasticity	Increased perisynaptic and decreased somatic expression in epilepsy Upregulated in reactive astrocytes after seizures Altered synaptic plasticity and glutamate receptor expression in knockout mice	15,103,140
SPARC	Radial glia, vasculature cells, astrocytes and microglia	Synaptogenesis and cortical lamination Inhibition of hevin synaptogenic action Synaptic maturation	Upregulated in reactive astrocytes after seizures Expressed by reactive human astrocytes near tumours and correlated with epilepsy Anxiety and antidepressant-like behaviours, increase in excitatory synapse function and impaired LTP in SPARC-knockout mice	140,150

ADAMTs, a disintegrin and metalloproteinase with thrombospondin motifs; CS–GAG, chondroitin sulfate–glycosaminoglycan; CSPG, chondroitin sulfate proteoglycan; DGC, dentate granule cell; ECM, extracellular matrix; HA, hyaluronic acid; HSPG, heparin sulfate proteoglycan; LTP, long-term potentiation; MMP, matrix metalloproteinase; PNN, perineuronal net; PV⁺, parvalbumin positive; SPARC, secreted protein acidic and rich in cysteine; TLE, temporal lobe epilepsy; tPA, tissue plasminogen activator; TSP, thrombospondin.