Baram, Tallie Z

Brewster, Amy L

Custodio, Elyzabeth

Dube, Celine M

Richichi, Cristina

eScholarship - University of California

UC IrvineUC Irvine Previously Published WorksTitleSeizure susceptibility and epileptogenesis in HCN1-deficient mice: Electrophysiological and molecular characterizationPermalinkhttps://escholarship.org/uc/item/69b4v39mJournalEPILEPSIA, 47ISSN0013-9580AuthorsDube, Celine MBrewster, Amy LRichichi, Cristinaet al.Publication Date2006Copyright InformationThis work is made available under the terms of a Creative Commons Attribution License, availalbe at https://creativecommons.org/licenses/by/4.0/ Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of California3.020SEIZURE SUSCEPTIBILITY AND EPILEPTOGENESIS INHCN1-DEFICIENT MICE: ELECTROPHYSIOLOGICAL ANDMOLECULAR CHARACTERIZATIONCéline M. Dubé, Amy L. Brewster, Cristina Richichi, Elyzabeth Cus-todio, and Tallie Z. Baram (Anatomy & Neurobiology and Pediatrics,University of California at Irvine, Irvine, CA)Rationale: The current conducted by HCN channels (Ih) contributesto neuronal and network properties of the hippocampal formation. HCNchannels are expressed in diverse hippocampal interneuronal and prin-cipal cell populations. Their function depends on their subcellular dis-tribution and the hyper-or depolarizing nature of synaptic input (Santoroand Baram, 2003). We previously showed that experimental prolongedfebrile seizures (FS) in immature rats causes an enduring downregulationof HCN1 channel expression and leads to a hyperexcitable hippocam-pal network. Frank epilepsy develops in 35% of rats (Brewster et al.,2002, 2005; Dubé et al., 2006). The generation of HCN1-deficient mice(HCN1-/-) provides a powerful tool to examine the potential causal roleof reduced HCN1 channels in this hippocampal network dysfunction.These studies examined whether immature HCN1-/- mice are more sen-sitive to seizure provocation and prone to develop spontaneous recurrentseizures as adults. Concurrently, we examined the developmental ex-pression and seizure-evoked regulation of the remaining hippocampalHCN isoforms in these mice.Methods: The threshold temperature required for the onset of a hyper-thermic ‘febrile’ seizure was studied as a measure of hyperexcitability inHCN1-/- mice and wild-type controls. Experimental FS were induced onpostnatal day 14 and animals monitored as adults for the emergence ofspontaneous seizures using digital video hippocampal EEG recordings.Seizure events were determined according to both EEG (i.e., polyspikesor sharp-waves with amplitude > 200% of background lasting over 6 sec-onds) and behavioral criteria (i.e, freezing and ‘limbic’ automatisms).Hippocampal mRNA and protein expression of HCN channel isoforms1–4 was quantified using in situ hybridization and Western blots. The cellular and subcellular distribution of HCN isoforms was analyzed via immunocytochemistry.Results: Threshold temperatures for experimental FS onset in HCN1-/- mice were significantly higher than those of controls: 41.9 ± 0.2 ◦C (n = 22) vs 40.7 ± 0.2◦C (n = 24) p < 0.0001. These data indicate that HCN1-/- mice are less sensitive to seizure generation. EEGs were normal in all control mice and preliminary data have not yet revealed spontaneous seizures in HCN1-/- mice. Analyses of mRNA and pro-tein expression are ongoing, but preliminary data support an absence of compensatory changes in HCN2 and HCN4 (Nolan et al., 2004).Conclusions: These experiments suggest that global absence of HCN1 channels from all cell types and cellular compartments yields a ‘hypoexcitable’ network. In addition, they suggest that HCN1 channels contribute to hippocampal network properties in a complex manner that is dependent on the cell type (e.g., interneurons vs principal cells), sub-cellular compartment and perhaps developmental expression programs.(Supported by NIH NS 47993 (ALB); NS 35439 (TZB).)Epilepsia, Vol. 47, S4, 2006

English

Seizure susceptibility and epileptogenesis in HCN1-deficient mice: Electrophysiological and molecular characterization

https://escholarship.org/content/qt69b4v39m/qt69b4v39m.pdf?t=pyr0xx

Seizure susceptibility and epileptogenesis in HCN1-deficient mice: Electrophysiological and molecular characterization

Abstract

Similar works

Full text

Available Versions

eScholarship - University of California