Immune response and inflammation
Epileptic seizures are known to be associated with a range of immunological processes and with inflammation in the brain (32). Astrocytes contribute to these processes largely via the production of inflammatory substances such as chemokines and cytokines, particularly interleukin-1-beta (IL-1β) and tumour necrosis factor-alpha (TNF-α), and release these in association with epileptic activity (Fig. 1d) (32, 33). Moreover, inflammation can lead to changes in the expression of genes encoding various membrane proteins (channels, transporters and receptors) in astrocytes (33). Conformation changes of these can, in turn, enhance epileptic activity via the mechanisms outlined above.
Brain infections, especially bacterial abscesses and viral infections, are often associated with febrile seizures in childhood or with epileptic seizures. Here, too, it is probably the inflammatory process itself that increases the propensity for epileptic seizures rather than the causative agents per se (33).
Astrocytes express so-called toll-like receptors (TLR) that recognise and react to microbes (34, 35). Activation of these receptors can lead to stimulation of the transcription factor NFκB (nuclear factor «kappa-light-chain-enhancer» of activated B-cells), which can, in turn, increase astrocytic glutamate release (36).
Complex febrile seizures in children predispose to the development of temporal lobe epilepsy, and febrile seizures are associated with increased IL-1β levels in the central nervous system and serum (37). IL-1β increases excitability by enhancing glutamate receptor function and by inhibiting GABAergic transmission (32). In vitro experiments have shown that IL-1β and TNF-α act on astrocyte receptors to inhibit glutamate uptake and increase its secretion (38). During status epilepticus, activated microglia release IL-1β and TNF-α, which disrupt communication between astrocytes by downregulating gap junction proteins (39).
Astrocytes are thus involved in a number of inflammatory processes that can contribute to or trigger epileptic seizures.