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Dynamic changes of depolarizing GABA in a computational model of epileptogenic brain: Insight for Dravet syndrome
- Source :
- Experimental Neurology, Experimental Neurology, 2016, 283 (Pt A), pp.57-72. ⟨10.1016/j.expneurol.2016.05.037⟩, Experimental Neurology, Elsevier, 2016, 283 (Pt A), pp.57-72. 〈10.1016/j.expneurol.2016.05.037〉, Experimental Neurology, Elsevier, 2016, 283 (Pt A), pp.57-72. ⟨10.1016/j.expneurol.2016.05.037⟩
- Publication Year :
- 2016
- Publisher :
- HAL CCSD, 2016.
-
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.
- Subjects :
- 0301 basic medicine
Male
Epilepsies, Myoclonic
Synaptic Transmission
Dravet
Membrane Potentials
0302 clinical medicine
[ SDV.IB ] Life Sciences [q-bio]/Bioengineering
EEG
SCN1A
Child
gamma-Aminobutyric Acid
Paroxysmal depolarizing shift
GABAA receptor
Chemistry
musculoskeletal, neural, and ocular physiology
Pyramidal Cells
depolarizing GABA
Brain
Electroencephalography
stiripentol
medicine.anatomical_structure
Neurology
Child, Preschool
Anticonvulsants
Female
[SDV.IB]Life Sciences [q-bio]/Bioengineering
shunting inhibition
Shunting inhibition
medicine.drug
Interneuron
Adolescent
seizure
Models, Neurological
glutamate
interneuron
Inhibitory postsynaptic potential
Article
03 medical and health sciences
Developmental Neuroscience
Dravet syndrome
Stiripentol
medicine
Animals
Humans
Ictal
Computer Simulation
[SDV.IB] Life Sciences [q-bio]/Bioengineering
Neural Inhibition
medicine.disease
Brain Waves
NAV1.1 Voltage-Gated Sodium Channel
030104 developmental biology
nervous system
Mutation
excitatory GABA
epilepsy
fast-onset
Neuroscience
030217 neurology & neurosurgery
Subjects
Details
- Language :
- English
- ISSN :
- 00144886 and 10902430
- Database :
- OpenAIRE
- Journal :
- Experimental Neurology, Experimental Neurology, 2016, 283 (Pt A), pp.57-72. ⟨10.1016/j.expneurol.2016.05.037⟩, Experimental Neurology, Elsevier, 2016, 283 (Pt A), pp.57-72. 〈10.1016/j.expneurol.2016.05.037〉, Experimental Neurology, Elsevier, 2016, 283 (Pt A), pp.57-72. ⟨10.1016/j.expneurol.2016.05.037⟩
- Accession number :
- edsair.doi.dedup.....cb65d6a5444028fa6b900a4fbbfd666f