The Relationship between Astrocytes, Inflammation and Epileptogenesis

Abstract

Previous studies provided evidence that FSs in children increase the risk of epilepsy development. EFSs in animals confirmed this assumption. EFS generated with only hyperthermia induction caused astrocyte uncoupling, which was mediated by both reduced protein expression and alteration in the phosphorylation state of Cx43. These findings provide a mechanistic link between FSs and the development of epilepsy. EFS-induced inhibition of interastrocytic communication might be the consequence of inflammation via microglial activation. Astrocyte uncoupling occurs in the absence of neuronal death and astrogliosis, which suggests that these different aspects of astrocyte pathology are not mechanistically linked. EFSs generated with hyperthermia preceded by inflammation (DH experiments) did not increase the astrocyte uncoupling and did not influence the incidence of epilepsy.<br /> There is increasing evidence suggesting that inflammation promotes epileptogenesis. TAK1 deletion and inhibition have been shown to reduce inflammation. TAK1 activation was investigated in astrocytes and microglia at different time points after status epilepticus. TAK1 was found to be activated in microglia, but not in astrocytes, in a time-dependent manner after status epilepticus. Therefore, in the second part of the study the role of inflammation in epileptogenesis was investigated via TAK1 deletion in microglia. TAK1 deletion in microglia resulted in reduced CNS inflammation. In microglia-specific TAK1KO animals the frequency of chronic seizures was significantly reduced. TAK1-dependent cytokine release from microglia, but not from astrocytes, might be involved in epileptogenesis.