Differential Tgf-Beta Signaling In Glial Subsets Underlies Il-6-Mediated Epileptogenesis In Mice

TGF-beta 1 is a master cytokine in immune regulation, orchestrating both pro-and anti-inflammatory reactions. Recent studies show that whereas TGF-beta 1 induces a quiescent microglia phenotype, it plays a pathogenic role in the neurovascular unit and triggers neuronal hyperexcitability and epileptogenesis. In this study, we show that, in primary glial cultures, TGF-beta signaling induces rapid upregulation of the cytokine IL-6 in astrocytes, but not in microglia, via enhanced expression, phosphorylation, and nuclear translocation of SMAD2/3. Electrophysiological recordings show that administration of IL-6 increases cortical excitability, culminating in epileptiform discharges in vitro and spontaneous seizures in C57BL/6 mice. Intracellular recordings from layer V pyramidal cells in neocortical slices obtained from IL-6-treated mice show that during epileptogenesis, the cells respond to repetitive orthodromic activation with prolonged after-depolarization with no apparent changes in intrinsic membrane properties. Notably, TGF-beta 1-induced IL-6 upregulation occurs in brains of FVB/N but not in brains of C57BL/6 mice. Overall, our data suggest that TGF-beta signaling in the brain can cause astrocyte activation whereby IL-6 upregulation results in dysregulation of astrocyte-neuronal interactions and neuronal hyperexcitability. Whereas IL-6 is epileptogenic in C57BL/6 mice, its upregulation by TGF-beta 1 is more profound in FVB/N mice characterized as a relatively more susceptible strain to seizure-induced cell death.