Depolarizing -aminobutyric acid contributes to glutamatergic network rewiring in epilepsy

作者：Kourdougli Nazim; Pellegrino Christophe; Renko Juho Matti; Khirug Stanislav; Chazal Genevieve; Kukko Lukjanov Tiina Kaisa; Lauri Sari E; Gaiarsa Jean Luc; Zhou Liang; Peret Angelique; Castren Eero; Tuominen Raimo K; Crepel Valerie; Rivera Claudio^*

来源：Annals of Neurology, 2017, 81(2): 251-265.

DOI：10.1002/ana.24870

ObjectiveRewiring of excitatory glutamatergic neuronal circuits is a major abnormality in epilepsy. Besides the rewiring of excitatory circuits, an abnormal depolarizing -aminobutyric acidergic (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 circuits.
MethodsOsmotic minipumps were used to infuse intracerebrally a specific inhibitor of depolarizing GABAergic transmission as well as a functionally blocking antibody toward 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 electroencephalographic and electrophysiological recordings were performed at day 5 and 2 months post-SE.
ResultsBlockade of NKCC1 after SE with the specific inhibitor bumetanide restored NKCC1 and KCC2 expression, normalized chloride homeostasis, and significantly reduced the glutamatergic rMF sprouting 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 (3 days) post-SE infusion of bumetanide reduced rMF sprouting and recurrent seizures in the chronic epileptic phase.
InterpretationOur findings show that early post-SE abnormal depolarizing GABA and p75(NTR) signaling fosters 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. Ann Neurol 2017;81:251-265

• 出版日期2017-2