Epileptic activity during early postnatal life in the AY-9944 model of atypical absence epilepsy

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Atypical absence epilepsy (AAE) is an intractable disorder characterized by slow spike-and-wave discharges in electroencephalograms (EEGs) and accompanied by severe cognitive dysfunction and neurodevelopmental or neurological deficits in humans. Administration of the cholesterol biosynthesis inhibitor AY-9944 (AY) during the postnatal developmental period induces AAE in animals; however, the neural mechanism of seizure development remains largely unknown. In this study, we characterized the cellular manifestations of AY-induced AAE in the mouse. Treatment of brain slices with AY increased membrane excitability of hippocampal CA1 neurons. AY treatment also increased input resistance of CA1 neurons during early postnatal days (PND) 5-10. However, these effects were not observed during late PND (14-21) or in adulthood (7-10 weeks). Notably, AY treatment elicited paroxysmal depolarizing shift (PDS)-like epileptiform discharges during the early postnatal period, but not during late PND or in adults. The PDS-like events were not compromised by application of glutamate or GABA receptor antagonists. However, the PDS-like events were abolished by blockage of voltage-gated Na+ channels. Hippocampal neurons isolated from an in vivo AY model of AAE showed similar PDS-like epileptiform discharges. Further, AY-treated neurons from T-type Ca2+ channel alpha 1G knockout (Ca(v)3.1(-/-)) mice, which do not exhibit typical absence seizures, showed similar PDS-like epileptiform discharges. These results demonstrate that PDS-like epileptiform discharges during the early postnatal period are dependent upon Na+ channels and are involved in the generation of AY-induced AAE, which is distinct from typical absence epilepsy. Our findings may aid our understanding of the pathophysiological mechanisms of clinical AAE in individuals, such as those with Lennox-Gastaut syndrome. (C) 2015 Elsevier Ltd. All rights reserved.
Publisher
CHURCHILL LIVINGSTONE
Issue Date
2015-05
Language
English
Article Type
Article
Keywords

LENNOX-GASTAUT-SYNDROME; AMYLOID PRECURSOR PROTEIN; TEMPORAL-LOBE EPILEPSY; ALZHEIMERS-DISEASE; NETWORK MECHANISMS; PYRAMIDAL NEURONS; RAT HIPPOCAMPUS; LIPID RAFTS; WAVE DISCHARGES; CA2+ CHANNELS

Citation

CELL CALCIUM, v.57, no.5-6, pp.376 - 384

ISSN
0143-4160
DOI
10.1016/j.ceca.2015.04.001
URI
http://hdl.handle.net/10203/199065
Appears in Collection
BiS-Journal Papers(저널논문)
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