title: 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 circuits, an abnormal depolarizing γ-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.
  
  
  METHODS
  Osmotic 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 (p75NTR). 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.
  
  
  RESULTS
  Blockade 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 p75NTRsignaling, as bumetanide application reduced SE-induced p75NTRexpression and functional blockade of p75NTRdecreased rMF sprouting. The early transient (3 days) post-SE infusion of bumetanide reduced rMF sprouting and recurrent seizures in the chronic epileptic phase.
  
  
  CONCLUSIONS
  Our findings show that early post-SE abnormal depolarizing GABA and p75NTRsignaling 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.
authors.affiliation: Inserm Unit 901, Inmed, Marseille, France.|Mixed Unit of Research S901, Aix-Marseille University, Marseille, France.
authors.forename: Nazim
authors.initials: N
authors.lastname: Kourdougli
authors.affiliation: Inserm Unit 901, Inmed, Marseille, France.|Mixed Unit of Research S901, Aix-Marseille University, Marseille, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Pellegrino
authors.affiliation: Division of Pharmacology and Pharmacotherapy, University of Helsinki, Helsinki, Finland.
authors.forename: Juho-Matti
authors.initials: JM
authors.lastname: Renko
authors.affiliation: Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Khirug
authors.affiliation: Inserm Unit 901, Inmed, Marseille, France.|Mixed Unit of Research S901, Aix-Marseille University, Marseille, France.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Chazal
authors.affiliation: Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Tiina-Kaisa
authors.initials: TK
authors.lastname: Kukko-Lukjanov
authors.affiliation: Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Sari E
authors.initials: SE
authors.lastname: Lauri
authors.affiliation: Inserm Unit 901, Inmed, Marseille, France.|Mixed Unit of Research S901, Aix-Marseille University, Marseille, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Gaiarsa
authors.affiliation: Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Inserm Unit 901, Inmed, Marseille, France.|Mixed Unit of Research S901, Aix-Marseille University, Marseille, France.
authors.forename: Angélique
authors.initials: A
authors.lastname: Peret
authors.affiliation: Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Eero
authors.initials: E
authors.lastname: Castrén
authors.affiliation: Division of Pharmacology and Pharmacotherapy, University of Helsinki, Helsinki, Finland.
authors.forename: Raimo K
authors.initials: RK
authors.lastname: Tuominen
authors.affiliation: Inserm Unit 901, Inmed, Marseille, France.|Mixed Unit of Research S901, Aix-Marseille University, Marseille, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Crépel
authors.affiliation: Inserm Unit 901, Inmed, Marseille, France.|Mixed Unit of Research S901, Aix-Marseille University, Marseille, France.|Neuroscience Center, University of Helsinki, Helsinki, Finland.
authors.forename: Claudio
authors.initials: C
authors.lastname: Rivera
mesh_terms: D000818:Animals; D002034:Bumetanide / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects*; D009419:Nerve Tissue Proteins; D051381:Rats; D017208:Rats, Wistar; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D064506:Solute Carrier Family 12, Member 2 / Q000187:drug effects*; D013226:Status Epilepticus / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D027981:Symporters / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000187:drug effects*; D000096922:K Cl- Cotransporters
chemical_list: D002034:Bumetanide; D009419:Nerve Tissue Proteins; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor; D049994:Sodium Potassium Chloride Symporter Inhibitors; D064506:Solute Carrier Family 12, Member 2; D027981:Symporters; D005680:gamma-Aminobutyric Acid; D000096922:K Cl- Cotransporters; C578879:Slc12a2 protein, rat; C068313:Ngfr protein, rat