title: Epileptic activity during early postnatal life in the AY-9944 model of atypical absence epilepsy.
abstract: 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 Ca(2+) channel α1G knockout (Cav3.1(-/-)) 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.
authors.affiliation: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
authors.forename: Seungmoon
authors.initials: S
authors.lastname: Jung
authors.affiliation: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea. Electronic address: yong@kaist.ac.kr.
authors.forename: Yong
authors.initials: Y
authors.lastname: Jeong
authors.affiliation: Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea; Department of Neurology, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital (SNUH), Seoul, Republic of Korea. Electronic address: clark.jeon@gmail.com.
authors.forename: Daejong
authors.initials: D
authors.lastname: Jeon
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000502:physiology*; D056547:CA1 Region, Hippocampal / Q000166:cytology / Q000502:physiology; D020747:Calcium Channels, T-Type / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D004569:Electroencephalography; D004832:Epilepsy, Absence / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000502:physiology; D018408:Patch-Clamp Techniques; D061566:Voltage-Gated Sodium Channels / Q000502:physiology; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride / Q000009:adverse effects*
chemical_list: D020747:Calcium Channels, T-Type; D061566:Voltage-Gated Sodium Channels; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride
keywords: AY-9944; Atypical absence epilepsy; Lennox–Gastaut syndrome; Paroxysmal depolarizing shift