Glial dysfunction in the pathology of temporal lobe epilepsy

Abstract

Epilepsy is a common neurological disorder characterized by periods of transient abnormal electrical brain activity, which manifests as behavioral symptoms known as epileptic seizures. Despite intense research, the underlying mechanisms that lead to the transition of a previously healthy brain into one characterized by epileptic discharges remain incompletely understood. However, research over the last decades indicates that neuroinflammatory processes could play a major role in epileptogenesis. Inflammation in the brain is primarily controlled by glial cells, particularly astrocytes and microglia, which become rapidly reactive in response to brain injury. Moreover, in mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS), a common form of focal epilepsy, astrocytes lose their ability to form functional gap junction (GJ) coupled networks, an important function required to maintain K+ homeostasis and thus to control neuronal excitability. The combination of a neuroinflammatory cascade together with impaired homeostatic functions in astrocytes could contribute to the development of epilepsy and provide a novel target for antiepileptogenic drug development. This doctoral thesis aimed to understand the contribution of astrocyte dysfunction and microglia-mediated immunity to epileptogenesis in a mouse model of MTLE-HS. <br /> Initially, this thesis addressed the molecular pathways underlying dysfunctional astrocyte coupling in the hippocampus during early epileptogenesis. More specifically, we could show that microglia-derived tumor necrosis factor (TNF)-alpha is rapidly released following an epileptogenic brain insult in mice and is primarily responsible for the loss of astrocyte coupling during early epileptogenesis. Surprisingly, microglia-specific TNF-alpha knock-out in mice did not affect seizure frequency and epilepsy-associated neurodegeneration, which could potentially be explained by antagonistic effects of TNF receptor 1 vs TNF receptor 2 signaling. In a next step, we could show that activation of TGF-beta receptor 1/activin receptor-like kinase 5 signaling is not responsible for astrocyte uncoupling and only marginally contributes to epileptogenesis in our MTLE-HS model. Finally, using mice lacking the astroglial GJ-forming connexin 30 and 43, the data of this thesis demonstrate that a dysfunctional astrocyte network causally contributes to epilepsy development. <br /> Overall, the data of this thesis indicate reactive microglia as major initiators of a detrimental neuroinflammatory cascade, in which aberrant TNF-alpha release leads to astrocyte network dysfunction and impaired ion homeostasis, thereby aggravating epileptogenesis. Targeted manipulation of TNF-alpha/TNF receptor 1 signaling and/or preservation of astroglial coupling may represent novel and effective antiepileptogenic treatment strategies.