title: Activation of GABAAreceptors controls mesiotemporal lobe epilepsy despite changes in chloride transporters expression: In vivo and in silico approach.
abstract: Mesiotemporal lobe Epilepsy (MTLE), the most frequent form of focal epilepsy, is often drug-resistant. Enriching the epileptic focus with GABA-releasing engineered cells has been proposed as a strategy to prevent seizures. However, ex vivo data from animal models and MTLE patients suggest that, due to changes in chloride homeostasis, GABAAreceptor activation is depolarizing and partly responsible for focal interictal discharges and seizure initiation. To understand how these two contradictory aspects of GABAergic neurotransmission coexist in MTLE, we used an established mouse model of MTLE presenting hippocampal sclerosis and recurrent hippocampal paroxysmal discharges (HPDs) 30-40days after a unilateral injection of kainate in the dorsal hippocampus. We first showed that injections of GABAAreceptor agonists either systemically or directly into hippocampus suppressed HPDs. Western-blotting and immunostaining revealed that levels of α1, α3 and γ2 GABAAreceptor subunits were increased in epileptic mice, compared to saline controls, while levels of R1 and R2 GABABreceptor subunits but also NR1, NR2A and NR2B NMDA receptor subunits and GluR1 and GluR2 AMPA receptor subunits were decreased. In addition, we showed that the expression of the transporter NKCC1, which load neurons with chloride, was increased, whereas KCC2, a chloride extruder, was decreased and that HPDs were suppressed by injection of blockers of NKCC1. These different changes were integrated in a numerical model, and in silico simulations supported the notion that chloride imbalance impair local inhibitory control of pyramidal neurons' activity in this model of MTLE. However, our numerical model also suggested that lasting activation of these receptors restore physiological intracellular chloride concentrations and suppress HPDs. Overall, our study suggests that activation of GABAAreceptor remains an effective antiepileptic strategy to suppress focal seizures in MTLE, and demonstrates that modeling and simulation studies provide new insights about the cellular and synaptic mechanisms of this disease.
authors.affiliation: INSERM, U1216, F-3800 Grenoble, France; Univ. Grenoble Alpes, Grenoble Institut des Neurosciences, F-38000 Grenoble, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Stamboulian-Platel
authors.affiliation: Rhenovia Pharma SAS, F-68200 Mulhouse, France; Laboratoire MIPS EA2332, Université de Haute Alsace, F-68200 Mulhouse, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Legendre
authors.affiliation: INSERM, U1216, F-3800 Grenoble, France; Univ. Grenoble Alpes, Grenoble Institut des Neurosciences, F-38000 Grenoble, France.
authors.forename: Tanguy
authors.initials: T
authors.lastname: Chabrol
authors.affiliation: INSERM, U1216, F-3800 Grenoble, France; Univ. Grenoble Alpes, Grenoble Institut des Neurosciences, F-38000 Grenoble, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Platel
authors.affiliation: Rhenovia Pharma SAS, F-68200 Mulhouse, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Pernot
authors.affiliation: SynapCell SAS, F-38700 La Tronche, France.
authors.forename: Venceslas
authors.initials: V
authors.lastname: Duveau
authors.affiliation: SynapCell SAS, F-38700 La Tronche, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Roucard
authors.affiliation: Rhenovia Pharma SAS, F-68200 Mulhouse, France; GCBS, Western University of Health Sciences, Pomona, CA 91766, USA.
authors.forename: Michel
authors.initials: M
authors.lastname: Baudry
authors.affiliation: INSERM, U1216, F-3800 Grenoble, France; Univ. Grenoble Alpes, Grenoble Institut des Neurosciences, F-38000 Grenoble, France. Electronic address: antoine.depaulis@ujf-grenoble.fr.
authors.forename: Antoine
authors.initials: A
authors.lastname: Depaulis
keywords: MTLE; Mouse; Numerical model; Protein expression; Synaptic transmission