The role of spreading depression in the development of chronic epilepsy

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Epilepsy is a debilitating neurological disorder affecting 50 million people worldwide. Despite a variety of medical treatment options, a third of epilepsy patients keep having uncontrolled seizures. Most epileptic seizures occur in the framework of so-called structural epilepsies that develop as a consequence of most varied initial brain- damaging insults such as stroke, intracranial bleeding (ICB), or brain infections. The optimal therapy of structural epilepsies would be their prevention. Yet, our knowledge of the mechanisms underlying the development of epilepsy, a process called epileptogenesis, has remained far from complete. There is evidence that seizures during acute medical conditions increase the risk of subsequent structural epilepsy. However, electroencephalographic studies (EEG) in the context of such conditions have shown that seizures are often also accompanied by spreading depolarizations, and depressions, respectively (SD). SD constitutes a near-complete depolarization of neurons leading to a breakdown of the cellular membrane potential, and consecutive depression of neuronal activity over minutes, up to hours. Despite its substantial effect size, the epileptogenic potential of SD has remained largely obscure. Due to EEG signal filtering standards in clinical epileptology, SD is even essentially undetectable in clinical EEG recordings. Using a multimodal experimental platform, this project will elucidate the role of SD in epileptogenesis. To this end, the project will employ the recent Theiler’s murine encephalomyelitis virus (TMEV) epilepsy mouse model mimicking real life conditions. The model encompasses epileptic seizures and SD during acute self-limiting encephalitis, and frequently develops into structural epilepsy. Combining chronic multi-region calcium imaging of neural network dynamics (GCaMP) with video-EEG monitoring in freely moving mice, SD and its association with seizures will be characterized at high neuroanatomical resolution across months, ranging from health to chronic epilepsy. Based on measured SD frequency and duration in a realistic disease setting, the project will, along with the mentioned multimodal recordings, employ fiber-guided timed and region-specific optogenetic elicitation (C1V1, ChR2) of SD in neocortex or hippocampus. This will allow a precise mechanistic evaluation of the epileptogenic potential of SD, in the presence or absence of brain inflammatory processes. The results of this project could lead to a paradigm shift in clinical epileptology, as the field widely views SD as a mere epiphenomenon of seizures with little or no disease modifying potential. Moreover, this project could potentially unveil new therapeutic targets for the prevention of structural epilepsies.