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Published on: January 29, 2018
Epileptic activity during early postnatal life in the AY-9944 model of atypical absence epilepsy
Seungmoon Jung1, Yong Jeong1, Daejong Jeon2
1Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
Insights
Atypical absence epilepsy (AAE) in mice is linked to early postnatal changes in hippocampal neuron excitability. These seizures involve sodium channels, not typical T-type calcium channels, differentiating them from other absence epilepsies.
Area of Science:
- Neuroscience
- Epilepsy Research
- Developmental Neuroscience
Background:
- Atypical absence epilepsy (AAE) is a severe neurological disorder characterized by specific EEG patterns and cognitive deficits.
- The underlying neural mechanisms of AAE development, particularly in response to cholesterol synthesis inhibitors like AY-9944, are not well understood.
- Understanding AAE is crucial for developing effective treatments for intractable epilepsy syndromes.
Purpose of the Study:
- To investigate the cellular mechanisms of AY-9944-induced Atypical Absence Epilepsy (AAE) in the early postnatal mouse brain.
- To characterize the electrophysiological changes in hippocampal neurons following AY-9944 treatment.
- To determine the ion channel dependencies of the observed epileptiform discharges.
Main Methods:
- Treatment of mouse brain slices with AY-9944 during different postnatal developmental periods.
- Electrophysiological recordings of hippocampal CA1 neurons to assess membrane excitability and input resistance.
- Analysis of AY-9944-induced epileptiform discharges and their sensitivity to pharmacological blockers.
- Comparison of AY-treated neurons from wild-type and Cav3.1 knockout mice.
Main Results:
- AY-9944 treatment increased hippocampal CA1 neuron excitability and input resistance during early postnatal days (PND 5-10).
- Early postnatal AY treatment induced paroxysmal depolarizing shift (PDS)-like epileptiform discharges, dependent on voltage-gated sodium channels.
- These AY-induced PDS-like events were independent of glutamate and GABA receptors and T-type calcium channels.
- Similar PDS-like discharges were observed in vivo and in AY-treated Cav3.1(-/-) mice.
Conclusions:
- AY-induced AAE in early postnatal mice involves Na+-dependent PDS-like epileptiform discharges, distinct from typical absence epilepsy mechanisms.
- These findings highlight a critical developmental window for AAE pathogenesis.
- The results offer insights into the pathophysiology of clinical AAE, potentially informing treatments for conditions like Lennox-Gastaut syndrome.
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.
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