title: AMPA receptor antagonist NBQX attenuates later-life epileptic seizures and autistic-like social deficits following neonatal seizures.
abstract: OBJECTIVE
  To determine whether AMPA receptor (AMPAR) antagonist NBQX can prevent early mammalian target of rapamycin (mTOR) pathway activation and long-term sequelae following neonatal seizures in rats, including later-life spontaneous recurrent seizures, CA3 mossy fiber sprouting, and autistic-like social deficits.
  
  
  METHODS
  Long-Evans rats experienced hypoxia-induced neonatal seizures (HS) at postnatal day (P)10. NBQX (20 mg/kg) was administered immediately following HS (every 12 h × 4 doses). Twelve hours post-HS, we assessed mTOR activation marker phosphorylated p70-S6 kinase (p-p70S6K) in hippocampus and cortex of vehicle (HS + V) or NBQX-treated post-HS rats (HS + N) versus littermate controls (C + V). Spontaneous seizure activity was compared between groups by epidural cortical electroencephalography (EEG) at P70-100. Aberrant mossy fiber sprouting was measured using Timm staining. Finally, we assessed behavior between P30 and P38.
  
  
  RESULTS
  Postseizure NBQX treatment significantly attenuated seizure-induced increases in p-p70S6K in the hippocampus (p < 0.01) and cortex (p < 0.001). Although spontaneous recurrent seizures increased in adulthood in HS + V rats compared to controls (3.22 ± 1 seizures/h; p = 0.03), NBQX significantly attenuated later-life seizures (0.14 ± 0.1 seizures/h; p = 0.046). HS + N rats showed less aberrant mossy fiber sprouting (115 ± 8.0%) than vehicle-treated post-HS rats (174 ± 10%, p = 0.004), compared to controls (normalized to 100%). Finally, NBQX treatment prevented alterations in later-life social behavior; post-HS rats showed significantly decreased preference for a novel over a familiar rat (71.0 ± 12 s) compared to controls (99.0 ± 15.6 s; p < 0.01), whereas HS + N rats showed social novelty preference similar to controls (114.3 ± 14.1 s).
  
  
  CONCLUSIONS
  Brief NBQX administration during the 48 h postseizure in P10 Long-Evans rats suppresses transient mTOR pathway activation and attenuates spontaneous recurrent seizures, social preference deficits, and mossy fiber sprouting observed in vehicle-treated adult rats after early life seizures. These results suggest that acute AMPAR antagonist treatment during the latent period immediately following neonatal HS can modify seizure-induced activation of mTOR, reduce the frequency of later-life seizures, and protect against CA3 mossy fiber sprouting and autistic-like social deficits.
authors.affiliation: Department of Neurology, Children's Hospital Boston and Harvard Medical School, Boston, Massachusetts, U.S.A; Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.
authors.forename: Jocelyn J
authors.initials: JJ
authors.lastname: Lippman-Bell
authors.forename: Sanjay N
authors.initials: SN
authors.lastname: Rakhade
authors.forename: Peter M
authors.initials: PM
authors.lastname: Klein
authors.forename: Makram
authors.initials: M
authors.lastname: Obeid
authors.forename: Michele C
authors.initials: MC
authors.lastname: Jackson
authors.forename: Annelise
authors.initials: A
authors.lastname: Joseph
authors.forename: Frances E
authors.initials: FE
authors.lastname: Jensen
mesh_terms: D000375:Aging; D000818:Animals; D000831:Animals, Newborn; D001321:Autistic Disorder / Q000188:drug therapy; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009474:Neurons / Q000378:metabolism*; D011810:Quinoxalines / Q000494:pharmacology*; D051381:Rats; D020318:Rats, Long-Evans; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D011810:Quinoxalines; D018091:Receptors, AMPA; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline
keywords: AMPA receptor antagonists; Autistic-like behavior; Early life seizures; Epileptogenesis; Hypoxic/ischemic encephalopathy