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Loss of Dendritic HCN1 Subunits Enhances Cortical Excitability and Epileptogenesis

Huang, Z; Walker, MC; Shah, MM; (2009) Loss of Dendritic HCN1 Subunits Enhances Cortical Excitability and Epileptogenesis. J NEUROSCI , 29 (35) 10979 - 10988. 10.1523/JNEUROSCI.1531-09.2009. Green open access

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Abstract

Hyperpolarization-activated cation nonselective 1 (HCN1) plasticity in entorhinal cortical (EC) and hippocampal pyramidal cell dendrites is a salient feature of temporal lobe epilepsy. However, the significance remains undetermined. We demonstrate that adult HCN1 null mice are more susceptible to kainic acid-induced seizures. After termination of these with an anticonvulsant, the mice also developed spontaneous behavioral seizures at a significantly more rapid rate than their wild-type littermates. This greater seizure susceptibility was accompanied by increased spontaneous activity in HCN1(-/-) EC layer III neurons. Dendritic I-h in these neurons was ablated, too. Consequentially, HCN1(-/-) dendrites were more excitable, despite having significantly more hyperpolarized resting membrane potentials (RMPs). In addition, the integration of EPSPs was enhanced considerably such that, at normal RMP, a 50 Hz train of EPSPs produced action potentials in HCN1(-/-) neurons. As a result of this enhanced pyramidal cell excitability, spontaneous EPSC frequency onto HCN1(-/-) neurons was considerably greater than that onto wild types, causing an imbalance between normal excitatory and inhibitory synaptic activity. These results suggest that dendritic HCN channels are likely to play a critical role in regulating cortical pyramidal cell excitability. Furthermore, these findings suggest that the reduction in dendritic HCN1 subunit expression during epileptogenesis is likely to facilitate the disorder.

Type: Article
Title: Loss of Dendritic HCN1 Subunits Enhances Cortical Excitability and Epileptogenesis
Open access status: An open access version is available from UCL Discovery
DOI: 10.1523/JNEUROSCI.1531-09.2009
Publisher version: http://dx.doi.org./10.1523/JNEUROSCI.1531-09.2009
Language: English
Additional information: Copyright © 2009 Society for Neuroscience 0270-6474/09/2910979-10$15.00/0 This article is freely available online through the J Neurosci Open Choice option
Keywords: TEMPORAL-LOBE EPILEPSY, CA1 PYRAMIDAL NEURONS, H-CHANNEL SUBUNITS, ENTORHINAL CORTEX, STATUS EPILEPTICUS, LAYER-III, INTEGRATIVE PROPERTIES, DISTAL DENDRITES, IN-VITRO, SEIZURES
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Pharmacology
URI: https://discovery.ucl.ac.uk/id/eprint/134465
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