Epileptic activity during early postnatal life in the AY-9944 model of atypical absence epilepsy. Issue 5 (May 2015)

• Record Type: Journal Article
• Authors: Jung, Seungmoon; Jeong, Yong; Jeon, Daejong
• Is Part Of: Cell calcium. Volume 57:Issue 5/6(2015)
• Page Start: 376
• Page End: 384
• Publication Date: 2015-05
• Subjects: AY-9944 -- Paroxysmal depolarizing shift -- Atypical absence epilepsy -- Lennox–Gastaut syndrome; Calcium -- Metabolism -- Periodicals; Vertebrates -- Physiology -- Periodicals; Calcium -- Physiological effect -- Periodicals; Cell physiology -- Periodicals; Calcium in the body -- Periodicals; 572.516
• DOI: 10.1016/j.ceca.2015.04.001
• Languages: English
• ISSNs: 0143-4160

Abstract

Graphical abstract: Highlights: We developed AY 9944 (AY)-induced in vitro model of atypical absence epilepsy. AY elicits paroxysmal depolarizing shift (PDS)-like epileptiform discharges (PDSs). AY-induced PDSs occur only during early developmental period. AY-induced PDSs are largely dependent upon Na + channels. Ca v 3.1 T-type Ca 2+ channels are not involved in AY-induced 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 ( 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.