Rapid and epileptogenic astrocyte morphology changes in the hippocampus

Abstract

Alterations in astrocytes are believed to contribute to the emergence and maintenance of epileptic activity. It has been demonstrated that astrocyte morphology in the hippocampus undergoes rapid changes within minutes following the induction of epileptic activity in established temporal lobe epilepsy (TLE) models. These morphological alterations persist beyond the epileptic activity and increase seizure susceptibility in vitro, an effect mediated by Rho-associated kinase (ROCK) signaling. However, the molecular trigger initiating these astrocytic changes remains unclear. The aim of this study was therefore to investigate potential signaling cascades linking epileptiform activity to rapid astrocyte morphology changes.<br /> Inflammation has been consistently linked to epileptic processes in the brain, making tumor necrosis factor alpha (TNFα) a promising candidate for investigating its effects on astrocytes. TNFα levels are elevated in epilepsy, and it is known to modulate cell morphology via ROCK signaling in various cell types.<br /> It was therefore investigated whether exogenous TNFα can rapidly induce astrocyte morphology changes in vitro, whether prolonged TNFα exposure affects astrocyte morphology, and whether epileptiform activity triggers rapid astrocyte morphology changes in the absence of TNFα receptor 1 (TNFR1). Additionally, it was examined whether brain-derived neurotrophic factor (BDNF) or norepinephrine (NE), both of which are increased in epileptic conditions and known to influence astrocyte morphology in various models, contribute to acute astrocyte morphology changes.<br /> Similar to preliminary data, these experiments utilized multiphoton fluorescence microscopy, electrophysiology, and pharmacology in acute hippocampal brain slices. Astrocyte morphology was specifically assessed using volume fraction measurements.The results indicate that TNFα neither acutely nor after prolonged exposure induces astrocyte morphology changes. Furthermore, it was demonstrated that epileptiform activity leads to rapid astrocytic remodeling even in the absence of TNFR1, suggesting that TNFα alone does not mediate these changes. Moreover, NE did not acutely alter astrocyte morphology, and BDNF had no effect after prolonged incubation.<br /> In conclusion, it is suggested that TNFα, NE, and BDNF are unlikely to be the primary triggers of rapid astrocytic morphology changes during epileptiform activity. Further research is needed to identify the underlying molecular mechanisms responsible for these alterations.