168 Chapter 7 glutamate release, supplying the environment with more excitotoxic molecules141. Astrocytic overexpression of P2X7 was also found in the white and grey matter in secondary progressive MS143 as well as upon stimulation with IL-1β114, suggesting that this signalling pathway is especially relevant during inflammation. P2X7 is also of importance in epilepsy, since sufferers have higher P2X7 expression than healthy controls in the neocortical nerve terminals. P2X7 antagonist treatment decreases the severity and number of epileptic seizures in rats144. Excitotoxicity is a relevant mechanism of cell death in many disorders, and astrocyte-oligodendrocyte cross-talk plays an important role here, as astrocytes are able to create a hostile environment with glutamate and ATP which then damages oligodendrocytes. Inhibition of astrocytic glutamate release or increasing the activity of the EAAT receptors may thus be a relevant treatment mechanism in epilepsy or white matter diseases. Astrocyte control of remyelination and the extracellular matrix Thewhitematterofthebrainprimarilyconsistsofmyelinatedaxonsformedbyoligodendrocytes, after differentiating from OPCs4. In demyelinating diseases such as MS and NMO, functional recovery requires remyelination. Although in these diseases astrocytes are known to be detrimental to oligodendrocytes and OPCs, they also promote and mediate remyelination7,44. For example, in vivo ablation of astrocytes results in impaired recovery from SCI2. In MS or SCI remyelination occurs but often fails despite the presence of significant numbers of OPCs suggesting the lack of remyelination is likely due to a failure in OPC differentiation rather than migration23,145,146. However, migration failure and clustering of OPCs at astrocyte endfeet indicates that astrocytes may also play a role in restricting migration of OPCs77. Recruitment of OPCs to the demyelinating area occurs through astrocyte chemokine signalling of IL-1β and CCL2, confirming the necessity of cellular cross-talk in remyelination23,147. After migration, OPCs exit the cell cycle and differentiate into oligodendrocytes through stimulation of PDGF and FGF-2146. FGF-2 is highly upregulated by astrocytes in remyelinating spinal cord lesions where it acts on oligodendrocytes as well as in autocrine fashion on astrocytes148. Recently, a new study has found that OPCs might not be as important for remyelination as previously thought. Remyelination was found to be mainly dependent on the pool of surviving mature oligodendrocytes present in the lesions based on carbon dating of oligodendrocytes149. Astrocytes influence oligodendrocytes via modification of the extracellular matrix (ECM). A major ECM component secreted by astrocytes is hyaluronan, which acts on T-cells and OPCs, blocking OPC differentiation into oligodendrocytes and promoting astrocytic differentiation44. Hyaluronan is especially abundant in white matter lesions of MS patients24, as well as patients with rare familial leukodystrophies VWM53 and AxD126. Exaggerated hyaluronan secretion is a common feature of leukodystrophies, and likely has a role in neurological pathogenesis. Another astrocytic ECM factor is laminin that controls the differentiation and migration of OPCs, and promotes their survival by binding integrin and dystroglycan receptors. Mutations in laminin result in profound muscular and white matter abnormalities150-152. In inflammatory conditions, reactive astrocytes also produce tenascin C and R. Tenascin C is linked to inhibition of OPC migration, but tenascin R induces myelin gene expression and OPC differentiation. In chronic MS plaques, both tenascin C and R were shown to be upregulated in reactive astrocytes152. Lastly, astrocytes secrete proteoglycans that inhibit remyelination in high concentrations153. Proteoglycans also capture chemokines and growth factors, localizing them and targeting immune cells to the area of inflammation. This helps to
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