Table 1.
Extracellular Molecules and ECM Remodeling Proteases in Epilepsy.
| Molecules | Sources | Functions | Changes in epilepsy |
|---|---|---|---|
| Chondroitin sulfate proteoglycans (CSPGs) | Neurons, astrocytes, and oligodendrocytes | PNN formation, cellular signaling, synaptic plasticity, axonal guidance, chloride ion homeostasis2,6,18-21 | Upregulated after epileptogenic insults and in epilepsy models and human TLE tissue5,6,10,22,23 |
| Aggrecan | Neurons and astrocytes | Cellular signaling and axon guidance, critical for PNN formation6,2,24,25 | PNN disruption, decreased expression and increase in MMP cleavage products6,7,12 |
| Neurocan | Neurons and astrocytes | Axonal path finding, cell adhesion, synapse formation, plasticity, PNN formation2,6,20 | Increased expression in TLE and animal models5,23,26 |
| Brevican | Neurons, astrocytes, and oligodendrocytes | PNN formation,20 ion channel expression, and functional regulation of PV neurons8,27,28 | Decreased in human epilepsy, increased cleavage by ADAMTs5,28 |
| Versican | Astrocytes and oligodendrocytes | PNN formation2,20 | Decreased expression5 |
| Tenascin-C | Astrocytes, neurons, radial glial, and epithelial cells | Synaptic plasticity, proliferation, and maturation of astrocytes | Increased expression after seizures and epileptogenic insults26,29,30 |
| Tenascin-R | Oligodendrocytes, neurons, and astrocytes | PNN formation and stability,2,31 synaptic plasticity, modulation of sodium channel activity, axonal conduction31 | Increased expression after lesion, injury, and seizure5,10 |
| Hyaluronan/hyaluronic acid (HA) | Neurons, astrocytes, high grade glioma, oligodendrocytes | PNN assembly, regulation of extracellular space, ion channel localization,27 cell migration and signaling | Upregulated expression, HA depletion or genetic deficiency causes seizures32-35 |
| Link proteins (HAPLNs) (Crtl1/Hapln1 and Bral-2/Hapln2) |
Neurons | Link CSPG and hyaluronic acid together to stabilize PNN structure2,36 | Decreased expression6,12 |
| Matrix metalloproteinases (MMPs 2, 3, 9) |
Astrocytes, endothelial cells, glioma, neurons, microglia, and oligodendrocytes | Developmental cell migration, regulation of PNN dynamics and ECM remodeling, dendritic morphology regulation, plasticity, regeneration, neuroprotection | Increased expression and activity, decreased seizure propensity in knockout and increased in MMP9 overexpressed mice, PNN disruption and epileptogenesis5,9,11,35,37-41 |
| A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTs) | Neurons, astrocytes, microglia, monocytes, and macrophages | Proteoglycanase/aggrecanase activity, neuroplasticity regulation and regeneration, inflammatory and antiangiogenic actions6 | Increased expression after epileptogenic insults5,6 |
| Tissue inhibitors of metalloproteinases (TIMPs) | Neurons and astrocytes | Regulation of MMPs activity | Increased after seizure activity40,42 |
| Tissue plasminogen activator (tPA) | Neurons and microglia | Serine protease activity, activate plasmin and MMPs, regulation of neuronal development and survival and synaptic function, synaptic plasticity | Upregulated in epilepsy, mossy fiber sprouting during epileptogenesis, reduced synaptic plasticity and delayed seizure progression in knockout mice6,10,35 |
Abbreviations: ADAMTs, a disintegrin and metalloproteinase with thrombospondin motifs; CSPG, chondroitin sulfate proteoglycan; ECM, extracellular matrix; HA, hyaluronic acid or hyaluronan; MMP, matrix metalloproteinase; PNN, perineuronal net; PV, parvalbumin; TLE, temporal lobe epilepsy.