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

Abstract

PURPOSE:

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.

KEY FINDINGS:

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).

SIGNIFICANCE:

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: Jocelyn J Lippman-Bell, Sanjay N Rakhade, Peter M Klein, Makram Obeid, Michele C Jackson, Annelise Joseph, Frances E Jensen
• Journal: Epilepsia (Epilepsia) Vol. 54 Issue 11 Pg. 1922-32 (Nov 2013) ISSN: 1528-1167 [Electronic] United States
• PMID: 24117347 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

Chemical References

• Quinoxalines
• Receptors, AMPA
• 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline

Topics

• Aging
• Animals
• Animals, Newborn
• Autistic Disorder (drug therapy)
• Behavior, Animal (drug effects, physiology)
• Disease Models, Animal
• Hippocampus (drug effects, metabolism, pathology)
• Male
• Neurons (metabolism)
• Quinoxalines (pharmacology)
• Rats
• Rats, Long-Evans
• Receptors, AMPA (antagonists & inhibitors, metabolism)
• Seizures (chemically induced, drug therapy, metabolism)