Cytokine-mediated inhibition of astrocyte gap junction coupling as a cause of temporal lobe epilepsy

• Applicant: Professor Dr. Christian Steinhäuser
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; Molecular Biology and Physiology of Neurons and Glial Cells ; Molecular and Cellular Neurology and Neuropathology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 511827070

Temporal lobe epilepsy (TLE) is the most common form of adult epilepsies. Current treatments only suppress seizures but do not cure the disorder, and are inefficient in more than 2/3 of the patients. Hence, new therapeutic strategies and targets are urgently needed. In this regard, astrocytes have attracted increasing attention during recent years, since it has become clear that they actively regulate neuronal excitability and synaptic transmission. We have previously shown that gap junction coupling between astrocytes, which plays a key role in buffering of enhanced extracellular K+ and glutamate levels during high neuronal activity, is rapidly impaired after initiation of experimental TLE, and completely absent in the chronic phase of the disease in both, patients and an animal model. Our recent data suggest that astrocyte uncoupling is mediated by the soluble form of the proinflammatory cytokine, TNFα. Remarkably, specific inhibition of soluble TNFα not only prevented seizure-induced uncoupling but also yielded significant antiepileptic and antiepileptogenic effects in our animal model. Thus, we hypothesize that release of microglial TNFα after an initial epileptogenic event triggers disruption of astrocytic gap junction coupling, which in turn plays a key role in the development and progression of TLE. To test this hypothesis, in the present application we will i) unravel the time course of cytokine expression and astrocyte uncoupling in experimental TLE, ii) test the microglial origin of TNFα and identify the molecular mechanism(s) of its influence on astrocyte functions, and iii) prove the crucial role of TNFα-induced astrocyte uncoupling as a cause of TLE. This project will increase our understanding of the mechanisms of epileptogenesis and elucidate the potential of targeting glial signaling pathways for developing new, disease-modifying therapeutic strategies.

• DFG Programme: Research Grants