Achucarro Seminars

10 Nov [2017]

at 13.00 CET

Inflammation and dysfunctional astrocytes as a cause of human temporal lobe epilepsy

Christian Steinhäuser

Institutes of Cellular Neurosciences, Medical Faculty, University of Bonn


Abstract

Glial cells are now recognized as active communication partners in the CNS, and this new perspective has rekindled the question of their role in pathology. Recently, we have compared functional properties of astrocytes in hippocampal specimens from patients with mesial temporal lobe epilepsy (MTLE) with and without hippocampal sclerosis (MTLE-HS). The data showed that the sclerotic human hippocampus is completely devoid of bona fide astrocytes and gap junction coupling, whereas coupled astrocytes were abundantly present in non-sclerotic specimens. Employing a new mouse model of MTLE-HS, we could also show that astrocytic uncoupling and the consequential impairment of K+ clearance temporally precede neuronal death and the onset of spontaneous seizure activity (Bedner et al. 2015, Brain 138:1208-22). We found similar uncoupling also in another seizure model, i.e. hyperthermia-induced febrile convulsions, providing strong evidence that this dysfunction represents a fundamental mechanism in epileptogenesis. Our current results suggest that inhibition of astrocyte coupling during the early phase of epileptogenesis is not caused by reduced levels of gap junction proteins but by changes in the phosphorylation status of Cx43, as evidenced by Western blot and mass spectrometric analyses. Proinflammatory molecules appeared to mediate this posttranslational modification of Cx43, since astrocyte uncoupling was absent in toll-like receptor 4 knockout mice, could be induced by cytokines in situ and in vivo, and could be rescued by intraperitoneal injection of Xpro1595, a specific inhibitor of soluble TNFα, or of the antiepileptic drug levetiracetam. These data challenge the commonly accepted neurocentric view of epileptogenesis and demonstrate that astrocytes may be the prime cause of this condition.

Supported by Deutsche Forschungsgemeinschaft (STE 552/3-1), European Commission (ERA-Net NEURON BrIE) and Bundesministerium für Bildung und Forschung (01EW1501B).


Activity partially supported by UPV/EHU.

Host: Jan Tonnesen

 

https://www.izn.uni-bonn.de/institute?set_language=en

 

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