Microglia-Derived TNFα Induces Connexin43 Gap Junction Uncoupling In Astrocytes And Promotes Epileptogenesis In Kainate-Induced Epilepsy

Peter Bedner1, Dilaware Khan1, Fabienne Lülsberg1, Parmveer Singh2, Sajjad Muhammad1, Christian Steinhäuser1

1 University of Bonn, Institute of Cellular Neuroscience, Medical Faculty, Bonn, North Rhine Westphalia, Germany
2 Plexxikon Inc., Berkeley, CA 94710, USA

Temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS) is characterized by a loss of astrocyte gap junction (GJ) coupling, leading to impaired spatial buffering of extracellular K+ and subsequent neuronal hyperactivity 1,2. Previous data from this lab demonstrates that inhibition of soluble TNFα with XPro1595 not only prevents the loss of astrocytic GJ coupling, but simultaneously impedes epileptogenesis in the intracortical kainate (KA) model of TLE1. However, the cellular origin of TNFα in our model is ill-defined, as it is well understood that not only microglia but also astrocytes, neurons and blood-borne macrophages can synthesize and release the cytokine. Here we therefore explored the time course of microglia activation and peripheral macrophage infiltration into the brain. In addition, the efficiency of GJ coupling and seizure activity were evaluated in microglia-specific transforming growth factor beta-activated kinase 1 (TAK1) knock-out mice and in wildtype mice after oral administration of the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622. We found indications of activated microglia only at 5d but not 4h post KA injection. Moreover, blood-borne CD169+/Iba1+ macrophages infiltrate the brain at 5d post KA. Interestingly, partial depletion of microglia using PLX5622 prevents astrocyte GJ uncoupling at 4h post KA injection, a time point at which GJ coupling in astrocytes is typically reduced by about 50%1. Moreover, PLX5622 treatment reduces seizure severity during status epilepticus. Finally, TAK1 deletion in microglia results in decreased microglia activation, interictal spiking as well as gamma-like activity in the EEG during the chronic phase of TLE. Together, our data suggest that dysfunctional microglia-astrocyte communication underlies epileptogenesis in experimental TLE.

  1. Bedner et al., Brain 2015;138(5):1208-1222.
  2. Wallraff et al., Journal of Neuroscience 2006;26(20):5438-47.