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Published on: March 31, 2015
Rapid loss of dendritic HCN channel expression in hippocampal pyramidal neurons following status epilepticus
Sangwook Jung1, Lindsay N Warner, Julika Pitsch
1Department of Neurology and Regional Epilepsy Center, University of Washington, Seattle, Washington 98104, USA.
Insights
Epilepsy involves loss of hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels. This study reveals HCN1 channel loss begins rapidly after seizures, potentially contributing to epileptogenesis.
Area of Science:
- Neuroscience
- Molecular Biology
- Channelopathies
Background:
- Epilepsy is linked to altered expression and function of HCN ion channels.
- Previous work indicated loss of HCN channel current (I(h)) and HCN1 protein in hippocampal neurons post-status epilepticus (SE).
Purpose of the Study:
- To determine the precise onset and mechanisms of HCN1 channel loss after SE.
- To investigate if HCN1 loss precedes spontaneous recurrent seizures and contributes to epileptogenesis.
Main Methods:
- Utilized pilocarpine-induced SE in vivo and an in vitro SE model.
- Investigated temporal dynamics of I(h) and HCN1 channel expression (protein and mRNA) in hippocampal neurons.
Main Results:
- Loss of I(h) and HCN1 channel expression commenced within an hour post-SE.
- Observed sequential events: dendritic internalization, delayed protein loss, and later mRNA downregulation.
- In vitro SE replicated the rapid loss of dendritic I(h), indicating it's not solely an in vivo phenomenon.
Conclusions:
- HCN1 channelopathy initiates rapidly and persists following SE.
- Mechanisms involve both transcriptional and non-transcriptional pathways.
- Early HCN1 channel loss may be a significant factor in epileptogenesis.
Abstract:
Epilepsy is associated with loss of expression and function of hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels. Previously, we showed that loss of HCN channel-mediated current (I(h)) occurred in the dendrites of CA1 hippocampal pyramidal neurons after pilocarpine-induced status epilepticus (SE), accompanied by loss of HCN1 channel protein expression. However, the precise onset and mechanistic basis of HCN1 channel loss post-SE was unclear, particularly whether it preceded the onset of spontaneous recurrent seizures and could contribute to epileptogenesis or development of the epileptic state. Here, we found that loss of I(h) and HCN1 channel expression began within an hour after SE and involved sequential processes of dendritic HCN1 channel internalization, delayed loss of protein expression, and later downregulation of mRNA expression. We also found that an in vitro SE model reproduced the rapid loss of dendritic I(h), demonstrating that this phenomenon was not specific to in vivo SE. Together, these results show that HCN1 channelopathy begins rapidly and persists after SE, involves both transcriptional and nontranscriptional mechanisms, and may be an early contributor to epileptogenesis.
