Dataset Information

AMPA receptor antagonist NBQX attenuates later-life epileptic seizures and autistic-like social deficits following neonatal seizures.

ABSTRACT: 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.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.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).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.

SUBMITTER: Lippman-Bell JJ

PROVIDER: S-EPMC4262152 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

AMPA receptor antagonist NBQX attenuates later-life epileptic seizures and autistic-like social deficits following neonatal seizures.

Lippman-Bell Jocelyn J JJ Rakhade Sanjay N SN Klein Peter M PM Obeid Makram M Jackson Michele C MC Joseph Annelise A Jensen Frances E FE

Epilepsia 20131001 11

<h4>Purpose</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 24117347

Similar Datasets

Project description:To study the development of epilepsy following hypoxia-induced neonatal seizures in Long-Evans rats and to establish the presence of spontaneous seizures in this model of early life seizures.Long-Evans rat pups were subjected to hypoxia-induced neonatal seizures at postnatal day 10 (P10). Epidural cortical electroencephalography (EEG) and hippocampal depth electrodes were used to detect the presence of seizures in later adulthood (> P60). In addition, subdermal wire electrode recordings were used to monitor age at onset and progression of seizures in the juvenile period, at intervals between P10 and P60. Timm staining was performed to evaluate mossy fiber sprouting in the hippocampi of P100 adult rats that had experienced neonatal seizures.In recordings made from adult rats (P60-180), the prevalence of epilepsy in cortical and hippocampal EEG recordings was 94.4% following early life hypoxic seizures. These spontaneous seizures were identified by characteristic spike and wave activity on EEG accompanied by behavioral arrest and facial automatisms (electroclinical seizures). Phenobarbital injection transiently abolished spontaneous seizures. EEG in the juvenile period (P10-60) showed that spontaneous seizures first occurred approximately 2 weeks after the initial episode of hypoxic seizures. Following this period, spontaneous seizure frequency and duration increased progressively with time. Furthermore, significantly increased sprouting of mossy fibers was observed in the CA3 pyramidal cell layer of the hippocampus in adult animals following hypoxia-induced neonatal seizures. Notably, Fluoro-Jade B staining confirmed that hypoxic seizures at P10 did not induce acute neuronal death.The rodent model of hypoxia-induced neonatal seizures leads to the development of epilepsy in later life, accompanied by increased mossy fiber sprouting. In addition, this model appears to exhibit a seizure-free latent period, following which there is a progressive increase in the frequency of electroclinical seizures.

Dataset Information

AMPA receptor antagonist NBQX attenuates later-life epileptic seizures and autistic-like social deficits following neonatal seizures.

Publications

AMPA receptor antagonist NBQX attenuates later-life epileptic seizures and autistic-like social deficits following neonatal seizures.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets