Activation of GABA(A) receptors controls mesiotemporal lobe epilepsy despite changes in chloride transporters expression: In vivo and in silico approach

作者：Stamboulian Platel Severine; Legendre Arnaud; Chabrol Tanguy; Platel Jean Claude; Pernot Fabien; Duveau Venceslas; Roucard Corinne; Baudry Michel; Depaulis Antoine^*

来源：Experimental Neurology, 2016, 284: 11-28.

DOI：10.1016/j.expneurol.2016.07.009

• Mouse
• Protein expression
• MILE
• Synaptic transmission
• Numerical model

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 MILE patients suggest that, due to changes in chloride homeostasis, GABA(A) receptor 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) 30-40 days after a unilateral injection of kainate in the dorsal hippocampus. We first showed that injections of GABAA receptor agonists either systemically or directly into hippocampus suppressed HPDs. Western-blotting and immunostaining revealed that levels of alpha 1, alpha 3 and gamma 2 GABAA receptor subunits were increased in epileptic mice, compared to saline controls, while levels of R1 and R2 GABA(B) receptor subunits but also NR1, NR2A and NR2B NMDA receptor subunits and GluR1 and G1uR2 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 GABAA receptor 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.

• 出版日期2016-10