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Depolarizing γ-aminobutyric acid contributes to glutamatergic network rewiring in epilepsy

Abstract : Objective: Rewiring of excitatory glutamatergic neuronal circuits is a major abnormality in epilepsy. Besides the rewiring of excitatory circuit, an abnormal depolarizing GABAergic drive has been hypothesized to participate in the epileptogenic processes. However, a remaining clinically relevant question is whether early post Status Epilepticus (SE) evoked chloride dysregulation is important for the remodeling of aberrant glutamatergic neuronal circuit. Methods: Osmotic mini-pumps were used to infuse intracerebrally a specific inhibitor of depolarizing GABAergic transmission as well as a functionally blocking antibody towards the pan-neurotrophin receptor p75 (p75 NTR). The compounds were infused between 2 and 5 days after pilocarpine-induced SE. Immunohistochemistry for NKCC1, KCC2 and ectopic recurrent mossy fiber (rMF) sprouting as well as telemetric EEG and electrophysiological recordings were performed at day 5 and 2 months post-SE. Results: Blockade of NKCC1 after SE with the specific inhibitor bumetanide restored NKCC1 and KCC2 expression, normalized chloride homeostasis and significantly reduced the glutamatergic recurrent mossy fiber sprouting (rMF) within the dentate gyrus. This mechanism partially involves p75 NTR signaling as bumetanide application reduced SE-induced p75 NTR expression and functional blockade of p75 NTR decreased rMF sprouting. The early transient (3days) post-SE infusion of bumetanide reduced rMF sprouting and recurrent seizures in the chronic epileptic phase. Interpretation: Our findings show that early post-SE abnormal depolarizing GABA and p75 NTR signalings foster a long lasting rearrangement of glutamatergic network that contributes to the epileptogenic process. This finding defines promising and novel targets to constrain reactive glutamatergic network rewiring in adult epilepsy.
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Submitted on : Wednesday, December 26, 2018 - 2:21:06 PM
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Nazim Kourdougli, Christophe Pellegrino, Juho-Matti Renko, Stanislav Khirug, Geneviève Chazal, et al.. Depolarizing γ-aminobutyric acid contributes to glutamatergic network rewiring in epilepsy. Annals of Neurology, Wiley, 2017, 81 (2), pp.251-265. ⟨10.1002/ana.24870⟩. ⟨hal-01965606⟩

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