Dynamic changes of depolarizing GABA in a computational model of epileptogenic brain: Insight for Dravet syndrome

Abstract

Abnormal reemergence of depolarizing GABAA current during postnatal brain maturation may play a major role in paediatric epilepsies, Dravet syndrome (DS) being among the most severe. To study the impact of depolarizing GABA onto distinct patterns of EEG activity, we extended a neural mass model as follows: one sub-population of pyramidal cells was added as well as two sub-populations of interacting interneurons, perisomatic-projecting interneurons (basket-like) with fast synaptic kinetics GABAA (fast, I1) and dendritic-projecting interneurons with slow synaptic kinetics GABAA (slow, I2). Basket-like cells were interconnected to reproduce mutual inhibition mechanisms (I1➔I1). The firing rate of interneurons was adapted to mimic the genetic alteration of voltage gated sodium channels found in DS patients, SCN1A(+/-). We implemented the "dynamic depolarizing GABAA" mediated post-synaptic potential in the model, as some studies reported that the chloride reversal potential can switch from negative to more positive value depending on interneuron activity. The "shunting inhibition" promoted by GABAA receptor activation was also implemented. We found that increasing the proportion of depolarizing GABAA mediated IPSP (I1➔I1 and I1➔P) only (i.e., other parameters left unchanged) was sufficient to sequentially switch the EEG activity from background to (1) interictal isolated polymorphic epileptic spikes, (2) fast onset activity, (3) seizure like activity and (4) seizure termination. The interictal and ictal EEG patterns observed in 4 DS patients were reproduced by the model via tuning the amount of depolarizing GABAA postsynaptic potential. Finally, we implemented the modes of action of benzodiazepines and stiripentol, two drugs recommended in DS. Both drugs blocked seizure-like activity, partially and dose-dependently when applied separately, completely and with a synergic effect when combined, as has been observed in DS patients. This computational modeling study constitutes an innovative approach to better define the role of depolarizing GABA in infantile onset epilepsy and opens the way for new therapeutic hypotheses, especially in Dravet syndrome.

10.2174/1381612823666170809115827

“…However, other studies using Dravet Syndrome patient-derived induced pluripotent stem cells (iPSC) found increased excitability of both GABAergic and glutamatergic isolated neurons [280]. A recent study identified a depolarizing GABA phenomenon, and explored the mechanism of action of benzodiazepines and stiripentol, by using a physiology-based computational model [281]. Heterologous expression systems, in which cloned sodium channel α-subunits are expressed in an intrinsically non-excitable cell, were the first models used to investigate the cellular consequences of SCN1A mutations associated with epilepsy, and were the first to demonstrate that SCN1A mutations can cause both gain and loss of function at the channel level [282].…”

Personalization of hybrid brain models from neuroimaging and electrophysiology data

“…Since they can readily represent biophysics and physiology in a unified manner, HBMs can provide insights into the effects of brain stimulation techniques mediated by macro or mesoscale electric fields, such as tCS or TMS Merlet et al, 2013;Molaee-Ardekani et al, 2013;Muldoon et al, 2016;Kunze et al, 2016), or drugs (Kurbatova et al, 2016;Liang et al, 2015). This can be achieved as the individual level, and therefore could lead to the development of optimization and personalized treatment strategies.…”

“…We will first describe our construction of a template HBM, composed by a network of realistically interconnected Jansen and Rit (Jansen et al, 1993) NMMs which can simulate mesoscopic and macroscopic activity of the brain. We have also chosen this particular NMM because it can be tuned to simulate healthy or physio-pathological electric signals Kurbatova et al, 2016) and its possible response to interventions like transcranial current/magnetic stimulation (tCS, TMS) Merlet et al, 2013;Molaee-Ardekani et al, 2013;Kunze et al, 2016;Modolo et al, 2018) or drugs (Liang et al, 2015;Kurbatova et al, 2016). The main reason behind developing mesoscopic models of neural dynamics at the scale of whole brain is that experimental data is recorded at this scale (EEG, MRI).…”

Quantitative analysis and EEG markers of KCNT1 epilepsy of infancy with migrating focal seizures

“…The absence of mechanistic insight reduces the possibility of new specific therapeutic strategies. Our quantified index related to a very peculiar mode of seizure propagation in EIMFS might represent a key factor to generate realistic simulated seizures with neurophysiologically based computational modeling . Generation of simulated EIMFS able to reproduce similar TDI and PCI might reveal mechanistic insights and uncommon neurobiologic dysfunction that might be helpful for the development of new therapeutics.…”