Christopher Brian Currin 1, Henning Sprekeler 2, Joseph Valentino Raimondo 1
1. Human Biology, University of Cape Town, 1 Anzio Road, Cape Town, South Africa
2. Modelling of Cognitive Processes, Technische Universität Berlin, Marchstr. 23, Berlin, Germany
Seizures represent the result of highly synchronous and high frequency neural activity. Recurrent seizures are the hallmark of epilepsy, a debilitating disease, which affects 65 million people worldwide (Hirtz et al., 2007). The most severe form of an epileptic seizure is a state called status epilepticus (SE), which is characterised by unrelenting seizure activity that does not stop of its own accord (Sirven 2015).
The first-line treatment for SE uses a class of anti-convulsants known as benzodiazepines that target γ-aminobutyric acid (GABA) receptors, yet they only appear to have a ≈ 50% efficacy rate (Chin et al., 2008). Failure to terminate a seizure, either spontaneously or by application of anti-convulsants, can lead to persistent synchronous activity which results in significant morbidity and even mortality (Boggs, 2004).
Given the severe implications of SE, investigation into the mechanisms underlying its possible persistence, despite benzodiazepine application, is needed. Here, we construct a computational model with synaptic plasticity and dynamic chloride ions (Cl-) that is constrained by an experimental slice model of SE-like activity (Burman et al., 2019).
Here we demonstrate that 1) elevated [Cl-]i is sufficient to have a balanced network enter a SE-like state, 2) the model recapitulates experimental findings (Burman et al., 2019) in that SE-like activity is resistant to increases in GABAA receptor conductance (akin to benzodiazepine treatment), 3) recovery from SE can be facilitated by strong Cl- extrusion with the application of positive GABA conductance modulation, and 4) SE is driven by elevated [Cl-]i in pyramidal cells while interneuron Cl- has a minor influence. Together, these results provide clues to the mechanisms and potential therapies for status epilepticus.
The German Academic Exchange Service or DAAD (German: Deutscher Akademischer Austauschdienst) for awarding me funding to perform research in Berlin during 2018.
Thanks to the National Research Foundation (NRF) of South Africa and the University of Cape Town for funding this research.
Hirtz et al., 2007 - 10.1212/01.wnl.0000252807.38124.a3
Sirven 2015 - 10.1212/01.wnl.0000252807.38124.a3
Chin et al., 2008 - 10.1016/S1474-4422(08)70141-8
Boggs, 2004 - 10.1111/j.1535-7597.2004.04110.x
Burman et al., 2019 - 10.1093/brain/awz283
Brain disease, network dysfunction and intervention